Immune checkpoint inhibitor-related cholangiopathy: Novel clinicopathological description of a multi-centre cohort.

BACKGROUND AND AIMS: Cholestatic liver dysfunction is common in immune-related hepatitis (irH) during treatment with immune checkpoint inhibitors (CPI) for malignancy. We investigated the spectrum of bile duct injury and associated natural history in this cohort. METHOD: Clinical, laboratory, radiological and histopathological data in patients with evidence of bile duct injury during CPI treatment from 2018 to 2020 was collected in three tertiary hospitals. RESULTS: In this study, ten patients with confirmed bile duct disease were identified. Pembrolizumab was most commonly implicated (8/10). Median CPI cycles prior to bile duct injury was 6. Median alanine aminotransferase and alkaline phosphatase were 225 U/L and 1549 U/L respectively. Clinical jaundice was seen in 6/10 and radiological evidence of bile duct pathology in 8/10. Of five patients, who had liver biopsy, three cases (including two cases with normal MRCP) showed primary sclerosing cholangitis (PSC) like changes with periductal fibrosis. All patients were treated first-line with prednisolone following cessation of CPI, three with mycophenolate mofetil and one with tacrolimus, with clinical response in four patients. Five patients died after a mean follow-up of 27 weeks; cause of death was primarily related to progression of malignancy. CONCLUSION: Within this heterogeneous cohort, we identified that CPI-related cholangiopathy responded poorly to immunosuppression and potentially progressed to bile duct loss. Thorough radiological and histological assessment is recommended, as identification of the cholangiopathy-associated phenotype may permit more informed advice regarding prognosis. Further data is required to determine detailed immunological characterisation in order to identify individuals at an increased risk of developing cholangiopathy.

Vanishing bile duct syndrome associated with pazopanib after progression on pembrolizumab.

Pazopanib, a tyrosine kinase inhibitor, has been a standard first-line treatment for metastatic renal cell carcinoma (mRCC). Recent trials combining pazopanib with programmed cell death protein 1 (PD-1) inhibitors, including pembrolizumab, have shown excessive hepatotoxicity. We report a case of fatal hepatotoxicity from vanishing bile duct syndrome (VBDS) associated with pazopanib treatment, in a patient previously exposed to pembrolizumab. This is the first report of pazopanib-induced VBDS. We postulate whether prior exposure to pembrolizumab predisposed towards pazopanib-induction of VBDS, and discuss potential risks of sequential PD-1 inhibitor followed by pazopanib in mRCC, due to prolonged half-lives of PD-1 inhibitors.

Adverse events in people taking macrolide antibiotics versus placebo for any indication.

BACKGROUND: Macrolide antibiotics (macrolides) are among the most commonly prescribed antibiotics worldwide and are used for a wide range of infections. However, macrolides also expose people to the risk of adverse events. The current understanding of adverse events is mostly derived from observational studies, which are subject to bias because it is hard to distinguish events caused by antibiotics from events caused by the diseases being treated. Because adverse events are treatment-specific, rather than disease-specific, it is possible to increase the number of adverse events available for analysis by combining randomised controlled trials (RCTs) of the same treatment across different diseases. OBJECTIVES: To quantify the incidences of reported adverse events in people taking macrolide antibiotics compared to placebo for any indication. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), which includes the Cochrane Acute Respiratory Infections Group Specialised Register (2018, Issue 4); MEDLINE (Ovid, from 1946 to 8 May 2018); Embase (from 2010 to 8 May 2018); CINAHL (from 1981 to 8 May 2018); LILACS (from 1982 to 8 May 2018); and Web of Science (from 1955 to 8 May 2018). We searched clinical trial registries for current and completed trials (9 May 2018) and checked the reference lists of included studies and of previous Cochrane Reviews on macrolides. SELECTION CRITERIA: We included RCTs that compared a macrolide antibiotic to placebo for any indication. We included trials using any of the four most commonly used macrolide antibiotics: azithromycin, clarithromycin, erythromycin, or roxithromycin. Macrolides could be administered by any route. Concomitant medications were permitted provided they were equally available to both treatment and comparison groups. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted and collected data. We assessed the risk of bias of all included studies and the quality of evidence for each outcome of interest. We analysed specific adverse events, deaths, and subsequent carriage of macrolide-resistant bacteria separately. The study participant was the unit of analysis for each adverse event. Any specific adverse events that occurred in 5% or more of any group were reported. We undertook a meta-analysis when three or more included studies reported a specific adverse event. MAIN RESULTS: We included 183 studies with a total of 252,886 participants (range 40 to 190,238). The indications for macrolide antibiotics varied greatly, with most studies using macrolides for the treatment or prevention of either acute respiratory tract infections, cardiovascular diseases, chronic respiratory diseases, gastrointestinal conditions, or urogynaecological problems. Most trials were conducted in secondary care settings. Azithromycin and erythromycin were more commonly studied than clarithromycin and roxithromycin.Most studies (89%) reported some adverse events or at least stated that no adverse events were observed.Gastrointestinal adverse events were the most commonly reported type of adverse event. Compared to placebo, macrolides caused more diarrhoea (odds ratio (OR) 1.70, 95% confidence interval (CI) 1.34 to 2.16; low-quality evidence); more abdominal pain (OR 1.66, 95% CI 1.22 to 2.26; low-quality evidence); and more nausea (OR 1.61, 95% CI 1.37 to 1.90; moderate-quality evidence). Vomiting (OR 1.27, 95% CI 1.04 to 1.56; moderate-quality evidence) and gastrointestinal disorders not otherwise specified (NOS) (OR 2.16, 95% CI 1.56 to 3.00; moderate-quality evidence) were also reported more often in participants taking macrolides compared to placebo.The number of additional people (absolute difference in risk) who experienced adverse events from macrolides was: gastrointestinal disorders NOS 85/1000; diarrhoea 72/1000; abdominal pain 62/1000; nausea 47/1000; and vomiting 23/1000.The number needed to treat for an additional harmful outcome (NNTH) ranged from 12 (95% CI 8 to 23) for gastrointestinal disorders NOS to 17 (9 to 47) for abdominal pain; 19 (12 to 33) for diarrhoea; 19 (13 to 30) for nausea; and 45 (22 to 295) for vomiting.There was no clear consistent difference in gastrointestinal adverse events between different types of macrolides or route of administration.Taste disturbances were reported more often by participants taking macrolide antibiotics, although there were wide confidence intervals and moderate heterogeneity (OR 4.95, 95% CI 1.64 to 14.93; I² = 46%; low-quality evidence).Compared with participants taking placebo, those taking macrolides experienced hearing loss more often, however only four studies reported this outcome (OR 1.30, 95% CI 1.00 to 1.70; I² = 0%; low-quality evidence).We did not find any evidence that macrolides caused more cardiac disorders (OR 0.87, 95% CI 0.54 to 1.40; very low-quality evidence); hepatobiliary disorders (OR 1.04, 95% CI 0.27 to 4.09; very low-quality evidence); or changes in liver enzymes (OR 1.56, 95% CI 0.73 to 3.37; very low-quality evidence) compared to placebo.We did not find any evidence that appetite loss, dizziness, headache, respiratory symptoms, blood infections, skin and soft tissue infections, itching, or rashes were reported more often by participants treated with macrolides compared to placebo.Macrolides caused less cough (OR 0.57, 95% CI 0.40 to 0.80; moderate-quality evidence) and fewer respiratory tract infections (OR 0.70, 95% CI 0.62 to 0.80; moderate-quality evidence) compared to placebo, probably because these are not adverse events, but rather characteristics of the indications for the antibiotics. Less fever (OR 0.73, 95% 0.54 to 1.00; moderate-quality evidence) was also reported by participants taking macrolides compared to placebo, although these findings were non-significant.There was no increase in mortality in participants taking macrolides compared with placebo (OR 0.96, 95% 0.87 to 1.06; I² = 11%; low-quality evidence).Only 24 studies (13%) provided useful data on macrolide-resistant bacteria. Macrolide-resistant bacteria were more commonly identified among participants immediately after exposure to the antibiotic. However, differences in resistance thereafter were inconsistent.Pharmaceutical companies supplied the trial medication or funding, or both, for 91 trials. AUTHORS' CONCLUSIONS: The macrolides as a group clearly increased rates of gastrointestinal adverse events. Most trials made at least some statement about adverse events, such as "none were observed". However, few trials clearly listed adverse events as outcomes, reported on the methods used for eliciting adverse events, or even detailed the numbers of people who experienced adverse events in both the intervention and placebo group. This was especially true for the adverse event of bacterial resistance.

Magnetic resonance cholangiogram patterns and clinical profiles of ketamine-related cholangiopathy in drug users.

BACKGROUND & AIMS: Recreational ketamine use has emerged as an important health and social issue worldwide. Although ketamine is associated with biliary tract damage, the clinical and radiological profiles of ketamine-related cholangiopathy have not been well described. METHODS: Chinese individuals who had used ketamine recreationally at least twice per month for six months in the previous two years via a territory-wide community network of charitable organizations tackling substance abuse were recruited. Magnetic resonance cholangiography (MRC) was performed, and the findings were interpreted independently by two radiologists, with the findings analysed in association with clinical characteristics. RESULTS: Among the 343 ketamine users referred, 257 (74.9%) were recruited. The mean age and ketamine exposure duration were 28.7 (±5.8) and 10.5 (±3.7) years, respectively. A total of 159 (61.9%) had biliary tract anomalies on MRC, categorized as diffuse extrahepatic dilatation (n = 73), fusiform extrahepatic dilatation (n = 64), and intrahepatic ductal changes (n = 22) with no extrahepatic involvement. Serum alkaline phosphatase (ALP) level (odds ratio [OR] 1.007; 95% CI 1.002-1.102), lack of concomitant recreational drug use (OR 1.99; 95% CI 1.11-3.58), and prior emergency attendance for urinary symptoms (OR 1.95; 95% CI 1.03-3.70) had high predictive values for biliary anomalies on MRC. Among sole ketamine users, ALP level had an AUC of 0.800 in predicting biliary anomalies, with an optimal level of ≥113 U/L having a positive predictive value of 85.4%. Cholangiographic anomalies were reversible after ketamine abstinence, whereas decompensated cirrhosis and death were possible after prolonged exposure. CONCLUSIONS: We have identified distinctive MRC patterns in a large cohort of ketamine users. ALP level and lack of concomitant drug use predicted biliary anomalies, which were reversible after abstinence. The study findings may aid public health efforts in combating the growing epidemic of ketamine abuse. LAY SUMMARY: Recreational inhalation of ketamine is currently an important substance abuse issue worldwide, and can result in anomalies of the biliary system as demonstrated by magnetic resonance imaging. Although prolonged exposure may lead to further clinical deterioration, such biliary system anomalies might be reversible after ketamine abstinence. Clinical trial number: NCT02165488.

Clinical presentations and outcomes of bile duct loss caused by drugs and herbal and dietary supplements.

Bile duct loss during the course of drug-induced liver injury is uncommon, but can be an indication of vanishing bile duct syndrome (VBDS). In this work, we assess the frequency, causes, clinical features, and outcomes of cases of drug-induced liver injury with histologically proven bile duct loss. All cases of drug-induced liver injury enrolled into a prospective database over a 10-year period that had undergone liver biopsies (n = 363) were scored for the presence of bile duct loss and assessed for clinical and laboratory features, causes, and outcomes. Twenty-six of the 363 patients (7%) with drug-, herbal-, or dietary-supplement-associated liver injury had bile duct loss on liver biopsy, which was moderate to severe (<50% of portal areas with bile ducts) in 14 and mild (50%-75%) in 12. The presenting clinical features of the 26 cases varied, but the most common clinical pattern was a severe cholestatic hepatitis. The implicated agents included amoxicillin/clavulanate (n = 3), temozolomide (n = 3), various herbal products (n = 3), azithromycin (n = 2), and 15 other medications or dietary supplements. Compared to those without, those with bile duct loss were more likely to develop chronic liver injury (94% vs. 47%), which was usually cholestatic and sometimes severe. Five patients died and 2 others underwent liver transplantation for progressive cholestasis despite treatment with corticosteroids and ursodiol. The most predictive factor of poor outcome was the degree of bile duct loss on liver biopsy. CONCLUSION: Bile duct loss during acute cholestatic hepatitis is an ominous early indicator of possible VBDS, for which at present there are no known means of prevention or therapy. (Hepatology 2017;65:1267-1277).

The antifibrinolytic drug tranexamic acid reduces liver injury and fibrosis in a mouse model of chronic bile duct injury.

Hepatic fibrin deposition has been shown to inhibit hepatocellular injury in mice exposed to the bile duct toxicant α-naphthylisothiocyanate (ANIT). Degradation of fibrin clots by fibrinolysis controls the duration and extent of tissue fibrin deposition. Thus, we sought to determine the effect of treatment with the antifibrinolytic drug tranexamic acid (TA) and plasminogen activator inhibitor-1 (PAI-1) deficiency on ANIT-induced liver injury and fibrosis in mice. Plasmin-dependent lysis of fibrin clots was impaired in plasma from mice treated with TA (1200 mg/kg i.p., administered twice daily). Prophylactic TA administration reduced hepatic inflammation and hepatocellular necrosis in mice fed a diet containing 0.025% ANIT for 2 weeks. Hepatic type 1 collagen mRNA expression and deposition increased markedly in livers of mice fed ANIT diet for 4 weeks. To determine whether TA treatment could inhibit this progression of liver fibrosis, mice were fed ANIT diet for 4 weeks and treated with TA for the last 2 weeks. Interestingly, TA treatment largely prevented increased deposition of type 1 collagen in livers of mice fed ANIT diet for 4 weeks. In contrast, biliary hyperplasia/inflammation and liver fibrosis were significantly increased in PAI-1(-/-) mice fed ANIT diet for 4 weeks. Overall, the results indicate that fibrinolytic activity contributes to ANIT diet-induced liver injury and fibrosis in mice. In addition, these proof-of-principle studies suggest the possibility that therapeutic intervention with an antifibrinolytic drug could form a novel strategy to prevent or reduce liver injury and fibrosis in patients with liver disease.

Ketamine-related cholangiopathy: a retrospective study on clinical and imaging findings.

PURPOSE: Ketamine is a commonly abused recreational drug in Southeast Asia. There are emerging reports on ketamine abuse causing liver injury and biliary dilatation. This retrospective study aims to investigate the clinical and radiological features of this condition. METHODS: A retrospective search in the database of our institute was performed from January 2008 to February 2014 for patients who were ketamine abusers, with deranged liver function and/or epigastric pain, and had computed tomography of the abdomen or magnetic resonance cholangiopancreatography. Patient demographics, clinical data, and radiological findings were reviewed. RESULTS: Twenty-six patients (11 male and 15 female) were included in this study. Eighteen (69 %) patients had fusiform dilatation of the common bile ducts (CBDs) without evidence of intrinsic or extrinsic obstruction, and non-dilated intrahepatic ducts. The degree of CBD dilatation correlated with duration of abuse. In five patients who achieved abstinence, the CBD dilatation showed improvement. CONCLUSIONS: Ketamine-related cholangiopathy manifested as fusiform dilatation of the CBD without evidence of obstructive lesions. Severity of CBD dilatation appears to be correlated with the duration of ketamine, and the condition is potentially reversible in abstinent patients.

Dipeptidyl Peptidase-4 Inhibitors and the Risk of Gallbladder and Bile Duct Disease Among Patients with Type 2 Diabetes: A Population-Based Cohort Study.

INTRODUCTION: The use of dipeptidyl peptidase-4 (DPP-4) inhibitors may be associated with an increased risk of gallbladder and bile duct disease among patients with type 2 diabetes. METHODS: We conducted a population-based cohort study using an active comparator, new-user design. We used data from the United Kingdom Clinical Practice Research Datalink to identify patients newly treated with either a DPP-4 inhibitor or sodium-glucose cotransporter-2 (SGLT-2) inhibitor between January 2013 and December 2020. We fitted Cox proportional hazards models with propensity score fine stratification weighting to estimate the hazard ratio (HR) and its 95% confidence interval (CI) for incident gallbladder and bile duct disease associated with DPP-4 inhibitors compared to SGLT-2 inhibitors. RESULTS: DPP-4 inhibitors were associated with a 46% increased risk of gallbladder and bile duct disease (4.3 vs. 3.0 events per 1000 person-years, HR 1.46, 95% CI 1.17-1.83). At 6 months and 1 year, 745 and 948 patients, respectively, would need to be treated with DPP-4 inhibitors for one patient to experience a gallbladder or bile duct disease. CONCLUSIONS: In this population-based cohort study, the use of DPP-4 inhibitors, when compared with SGLT-2 inhibitors, was associated with a moderately increased risk of gallbladder and bile duct disease among patients with type 2 diabetes. This outcome was still quite rare with a high number needed to harm at 6 months and 1 year.

[Evaluation of clinical effectiveness of treatment of hepatobiliary disorders in the negative effects of environmental factors in children].

303 children with the diagnosis "Hepatobiliary disorders of cystic duct or gall bladder" and "Sphincter Oddu's spasm" have been examined. After a profound children's examination, the data of objective survey, and also laboratory, biochemical, immune, functional rates (such as ultrasound survey, cardiointervalography) and findings of chemical-analytical survey of the toxics rate (such as aroma carbons, phenol, aldehydes, aliphatic alcohols) in biospheres of children's organisms were a nalysed. The evaluation of the effectiveness of children's hepatobilliary disorders'treatment in conditions of the environmentae negative factors' influence.

Improvement of vanishing bile duct syndrome with hyperlipidemia.

A 75-year-old man was admitted to our hospital with acute onset of marked jaundice, elevated liver enzymes, and hyperlipidemia. He had been taking clopidogrel and pemafibrate for 3 months. He tested negative for autoantibodies and hepatitis-causing viruses. Gadoxetate-enhanced magnetic resonance imaging showed diffusely hypointense liver parenchyma in the hepatobiliary phase, with no appreciable excretion of gadoxetate into the biliary system. Histological examination of a liver specimen revealed disappearance of the bile ducts in the portal area and decreased expression of organic transporting polypeptide 1B3 on immunostaining. The patient was diagnosed with drug-induced vanishing bile duct syndrome and treated with ursodeoxycholic acid. The signs of liver dysfunction shown on blood chemistry tests improved spontaneously. After the acute hepatitis and lipid abnormalities had improved, repeat liver biopsy and gadoxetate-enhanced magnetic resonance imaging revealed improvement of the vanishing bile duct syndrome and recovery of the expression of organic transporting polypeptide 1B3. The reduction of OATP1B3 expression might be involved in the development of vanishing bile duct syndrome.

Vanishing bile duct syndrome following pembrolizumab infusion: case report and review of the literature.

PD-1/PD-L1 inhibitors demonstrate high efficacy in non-small-cell lung cancer and are now routinely used in clinical practice. Severe immune-related adverse events are reported in about 5% of patients, requiring hospitalization and possibly leading to death. We present a rare case of vanishing bile duct syndrome that arose a few days after the first pembrolizumab infusion. Laboratory tests and radiological imaging studies were performed to orient diagnosis and monitor the disease, while the evidence of ductal loss on the histological sample was pathognomonic for vanishing bile duct syndrome. High-dose steroid therapy and immunosuppressors were administered, resulting in scarce efficacy. Prompt recognition and management of similar conditions is crucial to avoid fatal events. Further studies are needed to investigate new drugs for steroid-refractory conditions.

Plain language summary Immunotherapy has demonstrated high efficacy in lung cancer and is commonly used in clinical practice. Despite the good tolerability, severe immune-related adverse events may occur, requiring hospitalization and possibly leading to death. We present a case of vanishing bile duct syndrome (a rare and potentially lethal condition characterized by progressive destruction of small bile ducts) which arose a few days after the first pembrolizumab infusion. Laboratory tests and radiological imaging were performed to orient diagnosis and monitor disease; a histological sample was required for vanishing bile duct syndrome diagnosis. High-dose steroid therapy and immunosuppressors were administered, with scarce efficacy. Prompt recognition and management of similar conditions is crucial to avoid fatal events. Further studies are needed to investigate new drugs for steroid-refractory conditions.

Hypertrophic cardiomyopathy and dysregulation of cardiac energetics in a mouse model of biliary fibrosis.

UNLABELLED: Cardiac dysfunction is a major cause of morbidity and mortality in patients with end-stage liver disease; yet the mechanisms remain largely unknown. We hypothesized that the complex interrelated impairments in cardiac structure and function secondary to progression of liver diseases involve alterations in signaling pathways engaged in cardiac energy metabolism and hypertrophy, augmented by direct effects of high circulating levels of bile acids. Biliary fibrosis was induced in male C57BL/6J mice by feeding a 0.1% 3,5-diethoxycarbonyl-1,4-dihydroxychollidine (DDC) supplemented diet. After 3 weeks, mice underwent live imaging (dual energy x-ray absorptiometry [DEXA] scanning, two-dimensional echocardiography [2DE], electrocardiography, cardiac magnetic resonance imaging), exercise treadmill testing, and histological and biochemical analyses of livers and hearts. Compared with chow-fed mice, DDC-fed mice fatigued earlier on the treadmill, with reduced VO(2). Marked changes were identified electrophysiologically (bradycardia and prolonged QT interval) and functionally (hyperdynamic left ventricular [LV] contractility along with increased LV thickness). Hearts of DDC-fed mice showed hypertrophic signaling (activation of v-akt murine thymoma viral oncogene/protein kinase B [AKT], inhibition of glycogen synthase kinase-3beta [GSK3beta], a 20-fold up-regulation of beta myosin heavy chain RNA and elevated G(s)alpha/G(i)alpha ratio. Genes regulating cardiac fatty acid oxidation pathways were suppressed, along with a threefold increase in myocardial glycogen content. Treatment of mouse cardiomyocytes (which express the membrane bile acid receptor TGR5) with potent natural TGR5 agonists, taurochenodeoxycholic acid and lithocholic acid, activated AKT and inhibited GSK3beta, similar to the changes seen in DDC-fed mouse hearts. This provides support for a novel mechanism whereby circulating natural bile acids can induce signaling pathways in heart associated with hypertrophy. CONCLUSION: Three weeks of DDC feeding-induced biliary fibrosis leads to multiple functional, metabolic, electrophysiological, and hypertrophic adaptations in the mouse heart, recapitulating some of the features of human cirrhotic cardiomyopathy.

Immunohistochemical characterization of macrophages and myofibroblasts in α-Naphthylisothiocyanate (ANIT)--induced bile duct injury and subsequent fibrogenesis in rats.

To investigate pathogenesis of post-bile duct (BD) injury fibrosis, interlobular BD epithelial injury was induced in male F344 rats by a single IP injection of α-naphthylisothiocyanate (75 mg/kg body weight) and rats were observed for 12 days. On days 1 to 2, cholangiocytes were injured and desquamated. On days 3 to 5, the affected BD began to regenerate, showing positive staining for CK19 and vimentin. On days 5 to 9, fibrotic areas gradually developed around regenerating BD in Glisson's sheath. These consisted of cells positive for vimentin, desmin, and α-SMA; vimentin- and desmin-positive cells were increased in early stage (days 1-3), whereas α-SMA-positive cells appeared in mid (days 4-7) and late stages (days 8-12), although there were cells coexpressing these cytoskeletons. On day 12, BD regeneration almost completed, with reduced fibrosis. Macrophages positive for ED2 (CD163) increased transiently in early stage, whereas those reacting to ED1 (CD68), OX6 (MHC II), and SRA-E5 (CD204) showed a consistent increase throughout the experiment. Interestingly, OX6-positive cells were limited to Glisson's sheath, whereas SRA-E5-positive cells were seen exclusively along sinusoids of hepatic lobules. MCP-1 mRNA increased significantly in early stage. This study shows that macrophages exhibiting different immunophenotypes and distributions participate in post-BD injury fibrosis associated with myofibroblasts expressing various mesenchymal cytoskeletons.

A Fatal Case of Toxic Epidermal Necrolysis Combined With Vanishing Bile Duct Syndrome and Hemophagocytic Lymphohistiocytosis.

This case report describes a case of fatal toxic epidermal necrolysis complicated by both vanishing bile duct syndrome and hemophagocytic lymphohistiocytosis due to Influenza B infection. Here we highlight the potential for complex morbidity secondary to underlying autoimmune hypersensitivity. Furthermore, the stepwise progression of these pathologies is noted, with the initial epidermal lesions first progressing to cholestatic injury and then subsequently to the hematologic manifestations.

Novel use of hepatobiliary scintigraphy for the diagnosis of interleukin-2 cholangiopathy.

We report a case of interleukin-2 (IL-2) induced cholangiopathy diagnosed with the aid of hepatobiliary scintigraphy. Patient was a 32 years old, male with history of metastatic melanoma. Computed tomography (CT) upon admission demonstrated worsening of patient's metastatic lung disease with a normal appearance of the gallbladder. The patient was started on high dose IL-2 treatment for regression of his disease. Four days after IL-2 treatment was begun, the patient developed severe right upper quadrant pain and elevated liver function tests. A right upper quadrant ultrasound and surgical consultation were requested. Sonographic findings demonstrated diffuse gallbladder wall thickening, mural edema, a positive sonographic Murphy's sign, but no gallstones. The preliminary working diagnosis was acalculous cholecystitis versus IL-2 induced cholangiopathy. To clarify between these two entities, a hepatobiliary scan was obtained that demonstrated filling of the gallbladder with prompt biliary-to-bowel transit and normal liver function. In this case, the clinical presentation and history of recent IL-2 treatment were suggestive of IL-2 cholangiopathy, though the patient's co-morbidities and in-patient status raised concern for acalculous cholecystitis. Given the marked differences in treatment, hepatobiliary imaging was requested and found to be normal, making acalculous cholecystitis very unlikely. In conclusion, we believe this is the first case in which hepatobiliary scintigraphy was used to aid in the diagnosis of IL-2 induced cholangiopathy.

Symptomatic Biliary Disorders During Lenvatinib Treatment for Thyroid Cancer: An Underestimated Problem.

Background: The prognosis of several human malignancies has dramatically improved after the introduction of tyrosine kinase inhibitors (TKIs); however, their use has been associated with a large spectrum of adverse events, including symptomatic biliary disorders. In the phase III trial of lenvatinib in radioactive iodine (RAI)-refractory differentiated thyroid cancer (DTC) patients, gallbladder (GB) and biliary duct (BD) diseases and complications were reported. We evaluated symptomatic biliary disorders during treatment with lenvatinib in real-life practice to provide a more exhaustive understanding of its toxicity. Methods: We retrospectively evaluated all consecutive patients treated with lenvatinib in our center for progressive RAI-refractory DTC, excluding those who underwent cholecystectomy before the start of therapy. We report all radiologically confirmed symptomatic GB/BD disorders, which were subsequently treated with cholecystectomy, and we describe their management along with relevant biochemical and histological findings. All available GB/BD imaging of patients who developed biliary toxicity during lenvatinib was reviewed by a single experienced radiologist, including computed tomography scans performed for tumor assessment at baseline and during TKI therapy. Results: Five patients (14.7%) developed symptomatic radiologically confirmed biliary disease after a median time of 4.4 months of lenvatinib treatment [interquartile range 3.4-14.4 months] and thus underwent cholecystectomy. A scheduled surgical approach was possible only in two cases; in the remaining patients, presurgical TKI interruption was shorter than one week. After wound healing, treatment was resumed by all subjects. Three patients showed mild biochemical alterations in the two previous monthly follow-up visits. Before the start of treatment, GB/BD abnormalities were radiologically detected only in one case. Conclusions: In our cohort, an unexpectedly high proportion of RAI-refractory DTC patients treated with lenvatinib developed a symptomatic biliary disorder with the need of surgical intervention. Further studies are required to optimize the diagnosis and treatment of patients at higher risk of developing a symptomatic GB/BD disease during assumption of lenvatinib.