Keywords

1 Hepatobiliary Toxicity

1.1 Nomenclature

The nomenclature used to describe hepatotoxicity associated with immune checkpoint inhibitors (ICIs) is variable. Examples of terms that have been used include “hepatic irAE” and “immune-mediated hepatitis.” The most recent review on this topic in Hepatology by Peeraphatdit et al. refers to this entity as “IMH” for “immune-mediated hepatotoxicity” [1]. Because bile ducts derive from the liver and with the knowledge that bile duct injury can occur simultaneously (or overlap) with hepatocellular injury, “immune-mediated hepatobiliary toxicity” or “ICI-mediated hepatobiliary toxicity” captures a broader spectrum of its heterogeneous presentations while maintaining the abbreviation of IMH for consistency and brevity. We will maintain this nomenclature henceforth.

1.2 Incidence

IMH is a well-recognized irAE [2]. The incidence of IMH varies depending on the ICI agent and whether monotherapy or dual ICI therapy is being employed. The overall incidence of hepatotoxicity associated with anti-PD-1/PD-L1 inhibitors is reported to be up to 12%, where the incidence of IMH associated with anti-PD-1 inhibitors (specifically pembrolizumab and cemiplimab) is relatively lower at 0.7–2.1% [1]. Anti-CTLA-4 inhibitors (most commonly ipilimumab) are associated with a hepatotoxic risk as low as 1–7% but as high as 16% [1, 3,4,5].

The risk of IMH increases up to 30% in patients receiving ICI combination therapy [3, 4, 6]. Grades 3–4 IMH were reported in 1–3% of patients receiving ICI monotherapy and in 8–14% of patients treated with a combination of anti-PD-1 and anti-CTLA-4 therapy [5,6,7,8,9,10,11,12,13]. Overall, the incidence of at least grade 3 IMH occurred in 1.1%, 1.7%, and 9.2%, associated with anti-PD-1/L1, anti-CTLA-4, and combination of ICI treatment, respectively [14]. Therefore, IMH is not an uncommon irAE. The diagnosis of grades 3–4 IMH has important implications for the patient’s future cancer treatment course and prospects for future candidacy for ICI treatment.

1.3 Pathophysiology

Aside from T-cell activation pathways that affect hepatocytes, the specific mechanism by which IMH develops is not understood. Hypotheses for mechanisms include the notion of a possible dose-dependent risk and permissive hepatotoxicity in those with preexisting autoimmune disease, although no studies have included those with idiopathic autoimmune hepatobiliary disease [1]. Currently, IMH is regarded as a form of “indirect” hepatotoxicity, which is not expected to be dose-related, but instead occuring due to the drug mechanism, which is immune-mediated [1]. IMH is not considered a form of idiosyncratic liver injury. Patient-specific risk factors and predictive models have not been identified. Interleukin-6 (IL-6) and its associated pathways have a well-described role in general liver biology, but the specific immunobiologic pathways to the development of IMH in relation to downstream signaling mechanisms have yet to be delineated. Because cholangiocytes express PD-L1, which would interact with PD-1 on activated T-cells, this may provide insight into possible mechanisms associated with cholangiopathic phenotypes of IMH. 

1.4 Clinical Presentation

IMH manifests along a spectrum of hepatocellular and/or cholestatic injury [11, 15,16,17]. The presentation of IMH remains highly heterogeneous, ranging from an asymptomatic state with the rise in liver enzymes to, rarely, death as a consequence of acute liver failure [18,19,20]. Although hepatotoxicity is commonly an incidental finding on routine laboratory screening during the course of ICI treatment, clinical signs and symptoms of IMH can include jaundice, acholic stool, malaise, abdominal pain, and fever [15, 21, 22]. Increased levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin are the commonly used biomarkers of IMH as suggested by the Common Terminology Criteria for Adverse Events (CTCAE)-based guidelines, regardless of the class of ICI [2, 5, 15, 19]. In general, IMH is often identified at about 5–13 weeks after initiation of ICI therapy, but its onset can be as early as after the first week [1, 13, 16, 19, 23]. IMH can also emerge after cessation of ICI therapy, which may depend on the half-life of the agent that was administered.

1.5 Diagnosis

1.5.1 Initial Diagnostic Evaluation

The diagnosis of IMH is approached in nearly the same manner as with other cases of suspected DILI. Like assessment for DILI in general, IMH is a diagnosis of exclusion. The clinician should perform a careful evaluation of the patient’s medical history including competing medications, the use of supplements (including herbal medications), and alcohol history. Other differential diagnoses should be explored and excluded [1, 5, 24]. These include viral etiologies (viral hepatitis A, B, C, or E; cytomegalovirus; Epstein-Barr virus; herpes simplex virus), idiopathic autoimmune liver disorders, and metabolic liver disorders (Wilson disease, hemochromatosis, and alpha-1 antitrypsin deficiency). Importantly, IMH is an entity that is distinct from idiopathic autoimmune hepatitis (AIH) and drug-induced AIH. AIH may be excluded when histologic features on liver biopsy are not compelling for AIH in conjunction with a normal total serum IgG level. In cases with cholestasis or jaundice, etiologies to be considered include acute liver dysfunction, choledocholithiasis, tumor causing obstructive jaundice, hemolytic disorder, or, rarely, IgG4-related cholangiopathy. In a patient of metastatic burden to the liver organ should be carefully considered.

Calculating the R factor will characterize the pattern of liver injury:

$$ \mathrm{R}\kern0.33em \mathrm{factor}=\frac{\left(\mathrm{ALT}/{\mathrm{ALT}}_{\mathrm{ULN}}\right)}{\left(\mathrm{ALP}/{\mathrm{ALP}}_{\mathrm{ULN}}\right)} $$

ALT, alanine aminotranferase; ALP, alkaline phosphatase; ULN, upper limit of normal.  Hepatocellular-predominant injury corresponds to an R factor greater than 5.0. Cholestatic-predominant injury corresponds to an R factor less than 2.0, when the ALP is at least 2× ULN. Mixed hepatocellular and cholestatic injury corresponds to an R factor from 2.0 to less than 5.0, when the ALT and ALP are both at least 2× ULN.

Based on both the magnitude of liver biochemical tests and the clinical presentation, the CTCAE version 5.0 grading is used to determine the specific management and/or treatment of IMH [25]. Liver enzymes include two transaminases (ALT and AST) and alkaline phosphatase. Liver function tests (LFTs) are the INR, total bilirubin, and albumin. From here forth, we will use the term “liver biochemical tests” (LBT) to refer to the combination of liver enzymes and liver function tests. In current society guidelines, the CTCAE grading of IMH is based on the ALT, AST, and total bilirubin. The standard criteria for CTCAE grading are summarized in Table 1.

Table 1 CTCAE (version 5.0) grading schema for liver biochemical laboratory tests
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The correct interpretation of the liver biochemical profile is crucial in the interpretation of the patient’s clinical status and planning the appropriate follow-up strategy [22]. ALT is more specific than AST as an indicator of hepatocellular injury, although, in general, the magnitudes of their levels are similar and track together over time. In DILI, the ALT level is generally similar or higher than the AST level. Because there is otherwise no universal standard ULN for the AST level, we recommend using the ULN of AST reported by the interpreting laboratory.

The alkaline phosphatase (ALP) level can be directly influenced by age, ethnicity, and the presence of metastatic disease to the liver or bone [26]. Society guidelines do not feature ALP in the overall CTCAE grading. However, significant ALP elevations should prompt further characterization to determine, for instance, whether the elevation is predominantly from a cholestatic condition or from bone turnover, which could be differentiated by first checking the GGT value. Alkaline phosphatase isoenzyme evaluation may also be helpful in some circumstances.

Any case of elevated bilirubin must be carefully characterized to determine whether it is associated with liver dysfunction, biliary obstruction, or another cause, because unconjugated hyperbilirubinemia may point toward a hematologic process (such as hemolysis) instead of impaired liver synthetic function. Therefore, this CTCAE grading should only be used when the direct bilirubin proportion is at least 50% of the total bilirubin, and after focal biliary obstruction is excluded. Serum albumin and INR levels should also contribute to the interpretation of liver synthetic function.

IMH is an entity that is distinct from idiopathic autoimmune hepatitis and drug-induced autoimmune hepatitis. There is no relationship between autoimmune serologic markers, such as ANA, with the diagnosis of IMH [1, 13]. AIH may be excluded when histologic features on liver biopsy are not compelling for AIH in conjunction with a normal total serum IgG level. The AIH scoring systems can be used to gauge this further [27]. The expectation would be that those patients with IMH should yield low-probability AIH scores. In the absence of positive AMA M2 type, normal total serum IgM level, and lack of typical histologic features such as florid duct lesions and ductopenia, primary biliary cholangitis can be excluded. The correct diagnosis of the observed laboratory derangements is crucial as it affects prognosis, indications for steroid treatment and its duration, clinical outcomes, and candidacy for ICI rechallenge.

1.5.2 Imaging

Abdominal imaging, such as computerized tomography (CT), magnetic resonance imaging (MRI), and abdominal ultrasound (US), must be part of the initial evaluation although findings in IMH are usually nonspecific [28]. Imaging can help detect alternative diagnoses such as liver metastasis, intrahepatic and extrahepatic biliary tree abnormalities, or vascular disease such as hepatic or portal vein thrombosis [15, 29, 30]. In patients who present with cholestasis suspicious for biliary tract disease, high-quality imaging targeting the biliary tree such as magnetic resonance cholangiopancreatography (MRCP) must be performed to exclude entities such as choledocholithiasis or other causes of obstructive jaundice. MRCP is also the preferred initial diagnostic imaging test for evaluating primary sclerosing cholangitis.

In general, IMH alone is associated with normal appearance of the liver or no new interval changes compared to prior liver imaging [15, 31]. However, reported radiological features in IMH that could manifest include periportal edema, hepatomegaly, periportal MRI T2 hyperintensity, attenuated liver parenchyma, and enlarged periportal lymph nodes on CT or MRI in severe IMH [15, 32, 33].

1.5.3 Role of Liver Biopsy and Interpretation of Histologic Features

The role of routine liver biopsy for diagnosing IMH is controversial since the liver biopsy is an invasive procedure [1, 34, 35]. Across published guidelines, liver biopsy has not been endorsed as an initial diagnostic test for confirmation of the diagnosis of IMH before treatment (i.e., steroids) is initiated. In clinical practice, if liver biopsy is not initially performed during the diagnostic phase, it may be considered later in those patients whose LBT fail to improve, either spontaneously or in response to systemic corticosteroid treatment.

There are currently no known pathognomonic histologic features of IMH. The most common histologic descriptions attributed to patients with IMH include nonspecific features of lobular or pan-lobular hepatitis, necroinflammatory findings that are either spotty or confluent, fibrin ring granulomas (particularly in those with anti-CTLA-4 exposure), central vein endotheliitis, prominent sinusoidal lymphohistiocytic infiltrates, and bile duct injury [10, 19, 21, 36, 37]. Despite their limitations, the histologic findings serve to exclude other causes of liver injury when the serologic data may not be revealing or may suggest a distinct, competing disease process under consideration. In a study of melanoma patients to gauge the utility of liver biopsy for suspected IMH, 58 patients with grades 3–4 liver injury underwent liver biopsy, three of whom were actually diagnosed with a condition other than IMH [38]. Whether or not the patient has positive autoimmune antibodies, the pattern of histologic inflammation could differentiate IMH from AIH. The finding of interface hepatitis with inflammatory cells that are plasma cell-predominant in AIH are distinct from the findings of lymphocyte and histiocyte predominance with typically lobular inflammation in IMH. In cases with cholestatic injury LBT patterns, the biopsy can confirm whether there is cholestasis and whether bile duct injury is seen in conjunction with hepatitis. If a patient's diagnostic work-up does reveal a positive autoimmune marker such as ANA, anti-smooth muscle antibody, or anti-mitochondrial antibody, then such a case would carry a very compelling indication to pursue a liver biopsy.

Although the diagnosis of IMH traditionally addresses hepatocellular injury, ICI-mediated bile duct injury is probably severely under-recognized as a distinct entity. In a case series of patients regarded as having immune checkpoint inhibitor-mediated hepatotoxicity, 56% of the cases had histologic evidence of bile duct injury [13]. The majority of such cases are reported in association with anti-PD-1 inhibitors, especially nivolumab and pembrolizumab [39,40,41,42,43,44,45]. Concomitant alkaline phosphatase elevations, jaundice, and histologic bile duct injury have been acknowledged in cases attributed traditionally to ICI-mediated “hepatotoxicity” [13, 46, 47]. Therefore, ICI-mediated cholangiopathy or cholangiohepatitis may exist within the spectrum of IMH. Its diagnosis can be corroborated by liver biopsy.

1.6 Management and Treatment Options

1.6.1 General Diagnostic Approach

The grading schema offered by the CTCAE version 5.0 influences the treatment approach to IMH [22, 48]. A primary limitation in the current treatment guidelines offered across multiple societies is that the recommendations are based on expert consensus without robust data. Given the dearth of evidence, monitoring and treatment strategies must be tailored to each patient’s specific scenario. Here, we offer our diagnostic algorithm and treatment recommendations based on existing guidelines, appraisal of published evidence, and our own clinical experience (Fig. 1).

Fig. 1
figure 1

Schema delineating the approach to the diagnosis of IMH and its treatment. The proposed steps reconcile current guidelines with the latest understanding from clinical experience. G grade (by CTCAE definitions), AZA azathioprine, MMF mycophenolate mofetil, LBT liver biochemical tests, AE adverse events or effects, IV intravenous

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  • Grade 1

Patients may continue ICI treatment with close monitoring of the LBT. Liver biopsy is not necessary to make the diagnosis.

  • Grade 2

ICI should be temporarily withheld with close monitor of the trends in LBT. Like in many cases of DILI, because spontaneous improvement could be observed in the short term, the first week may be used to initiate a more comprehensive liver disease workup, including the need to exclude acute infectious hepatitis, before deciding on steroid initiation. If LBT do not improve or worsen while remaining within grade 2 parameters, oral prednisone dosed at 0.5–1 mg/kg/day with maximum of oral prednisone 60 mg/day can be considered with a subsequent taper. Weekly lab monitoring is recommended.

  • Grade 3

ICI must be withheld. As part of the initial liver disease workup, liver biopsy should be considered to increase confidence for the diagnosis of IMH. Because grade 3 IMH has the potential to demonstrate spontaneous improvement, it is reasonable if not encouraged to monitor for signs of improvement in LBT for 1–2 weeks after recognition of LBT, during the diagnostic testing phase, before deciding to initiate steroids [14]. However, initiation of steroids should not be delayed once infection is confidently excluded and if LBT are not already improving.

Traditionally, a steroid dose range equivalent to either IV methylprednisolone or PO prednisone 1–2 mg/kg is suggested. The necessity of this dosing paradigm has been challenged [1, 49, 50]. We recommend a steroid range equivalent to prednisone of 0.5–1 mg/kg/day with maximum of oral prednisone 60 mg/day (regardless of patient weight) for induction [49,50,51]. If IV methylprednisolone is selected, then a dose of 60 mg/day can be administered. Weekly lab monitoring should be considered to track the evolution of changes in LBT. Once transaminases approach either complete biochemical remission or near biochemical remission (i.e., ALT of 2× ULN or less), steroids may then be tapered over 4–6 weeks, or longer, closely based on individual LBT trends [5, 52, 53].

  • Grade 4

ICI must be withheld. Thorough liver disease workup should be immediately pursued, including liver biopsy. Since grade 4 IMH also has the potential to demonstrate spontaneous improvement, barring evidence of liver failure, the patient’s LBT may be monitored for about 1 week while waiting for results from diagnostic testing before deciding to initiate steroids [14]. However, as with grade 3 IMH, if the LBT trends are not favorable by the end of the first week, initiation of corticosteroids should not be delayed if infection is not suspected or has been excluded. We generally recommend steroid dosing of the equivalent of prednisone 1 mg/kg/day, with maximum dose of oral prednisone 60 mg/day for induction. Steroids are eventually to be tapered once biochemical remission is achieved. It may take longer than 4–6 weeks depending on the starting dose of steroids and evolution of LBT. Close follow-up of laboratory values and careful examination for evidence of liver failure are key. If a patient demonstrates features of acute hepatic synthetic dysfunction (such as jaundice and significant elevation in the INR level), or if clinical features of acute liver failure are present (including presence of asterixis or an abrupt abnormal change in mental status), then hospitalization would be warranted to avoid delays in diagnosis and management.

In all patients initiated on the path of steroid treatment for IMH, we prefer prophylaxis against PJP pneumonia using atovaquone. Dapsone is an alternative. We avoid the use of trimethoprim-sulfamethoxazole, if possible, to lower the risk of hepatotoxicity. If the patient is not already on a proton pump inhibitor (PPI), a low dose of PPI should be prescribed for gastric protection while on steroids. Prolonged steroid use should prompt evaluation for glycemic control, particularly in patients who have an established diagnosis of prediabetes or diabetes.

1.6.2 Adjunctive Treatments

In patients initiated on steroids who do not respond satisfactorily after 3 days of treatment, clinicians should consider addition of adjunctive agent(s) to control IMH [1, 22, 23, 35, 54,55,56,57]. Many adjunctive therapies have been selected in real-world clinical use based on knowledge of an agent’s theoretical effects on targeting T-cell subpopulations [54]. Early or simultaneous adjunct treatment may also confer the benefit of a shorter time to ALT improvement in those with grade 3 IMH, thereby potentially reducing overall steroid exposure [58]. We prefer azathioprine (50–100 mg/day), which is established as a first-line adjunct treatment in idiopathic AIH, to be prescribed during the initial steroid induction phase [50, 58,59,60,61]. Ursodeoxycholic acid (UDCA or ursodiol), based on its mechanism and low risk of AE, may be prescribed in cases with cholestatic features, histologic bile duct injury, with or without jaundice [62,63,64]. The optimal dose of UDCA is not defined, although 13–15 mg/kg/day in divided doses can be adopted from the management of PBC.

The following agents and treatments have been published:

  • Mycophenolate mofetil [13, 14, 20, 34, 49, 54, 58, 62, 65,66,67,68,69,70]

  • Tocilizumab [44, 45, 71]

  • 6-mercaptopurine [19]

  • Tacrolimus [49, 54, 68]

  • Antithymocyte globulin (ATG) [20, 66, 72]

  • Plasma exchange [73]

  • Cyclosporine [59]

  • Budesonide [63]

  • Intravenous immunoglobulin (IVIG) [69, 70]

  • N-acetylcysteine [63]

  • Infliximab [49, 68]

To date, there are no studies comparing the relative efficacies of these agents. The potential adverse effects from the adjunctive agent utilized should be carefully weighed. Importantly, infliximab is not recommended to treat IMH due to its own potential hepatotoxicity [21, 22, 74, 100, 101]. Tocilizumab, an IL-6 receptor antagonist, has current applications in treating cytokine release syndrome and immunotherapy-mediated rheumatoid disease [35]. Along with emerging case reports to treat immunotherapy-mediated hepatobiliary disease, the use of tocilizumab may represent a favorable steroid-sparing strategy in cases of steroid-resistance or steroid-dependence, or in cases where serious adverse events develop from steroid use while treating IMH (Fig. 1). Additional focused studies for the use of tocilizumab in the context of IMH treatment are needed to demonstrate efficacy and safety. In summary, close and open communication amongst the hepatologist, the patient, and the oncologist is paramount in managing and monitoring IMH.

1.7 Outcomes

Treatment with corticosteroids will achieve improvement or normalization of liver enzymes in most patients [19, 37, 75]. Particularly in those with CTCAE grades 3–4 IMH, favorability of response to steroids is assessed over the first 3 days before reassessing the need to escalate treatment with higher steroid dose, immunomodulators, or other adjunctive agents, as suggested in current society guidelines. The median time from corticosteroid initiation to resolution is approximately 8 weeks [76].

In clinical practice, spontaneous resolution of IMH without corticosteroid therapy, including those with grades 3–4 liver injury, has been observed [13, 14, 77]. However, the factors that predict this favorable outcome are not yet defined. Therefore, most patients will ultimately go on to receive corticosteroids.

For patients undergoing steroid treatment, the first week after recognition of abnormal LBT offers a reasonable window to gauge whether the liver enzymes have or will soon reach its peak. LBT should be monitored at least once a week depending on the trends since AST and ALT may rebound even after completion of corticosteroid therapy and biochemical resolution. The utility of defining histologic remission in IMH has not been studied.

The timing and manner of steroid taper are important. Premature taper of steroids, particularly when the LBT have not adequately improved, could lead to rebound and uncontrolled IMH. This may lead to prolonging the current steroid dose or increasing the steroid dose to regain immunosuppression effects. As such, we generally recommend that the ALT and AST have both approached CTCAE grade 1 levels, but specifically less than 2× ULN (so that it is not immediately at the threshold with CTCAE grade 2 levels), before starting the taper from the initial induction dose (Fig. 1). In general, we recommend weekly tapering of each dose. The clinician should continue to monitor the LBT 1-2× per week during the taper through the date of completion of steroids (Fig. 1).

Liver failure and death related to IMH are rare [78,79,80,81,82]. The role of underlying liver disease such as metastatic tumor burden or cirrhosis (especially in patients with liver cancer) in the risk of IMH fatality has yet to be examined [30].

1.8 Rechallenging with ICI After Recovery From Grades 3–4 IMH

Society guidelines from NCCN, ASCO, SITC, ESMO, and AGA recommend permanent discontinuation of ICI for those who are diagnosed with grade 3 and grade 4 IMH [22, 35, 55,56,57, 100, 101]. This recommendation is based on expert consensus, but real-world experience and clinical practice challenge this paradigm. Available studies imply the opportunity for flexibility in patients where ICI was deemed effective but caused high grades IMH [14, 65, 83]. The risks, benefits, and alternative treatment options should be discussed with the patient and oncologist with expectation for very close pharmacovigilance. In efforts to attenuate the theoretical risk of ICI recurrence, the clinician may opt for monotherapy ICI rather than dual therapy with ICI rechallenge or resume ICI at a modified dose. Prophylactic use of adjunctive agents such as immunomodulators may also be considered. In our experience, careful ICI rechallenge guided by a multidisciplinary care team can often be successful.

1.9 Conclusions

IMH is increasingly encountered as ICI use becomes more expansive. It can occur as early as 1 week and as late as 13 weeks from initiation of ICI treatment. Delayed presentation of IMH is also possible depending on the half-life of the specific ICI. In most cases, IMH is asymptomatic and identified via routine lab surveillance. Potential symptoms, including abdominal pain, fever, jaundice, and malaise, are rare. Pharmacovigilance is paramount to permit early diagnosis. Mortality associated directly with IMH is rare.

As IMH remains a diagnosis of exclusion, other etiologies for new abnormal liver tests must be thoroughly explored. IMH is distinct from both idiopathic autoimmune hepatitis and drug-induced autoimmune hepatitis. No relationship to autoimmune markers is observed. Liver biopsy could be beneficial in select cases to corroborate a suspected case of IMH. Although no pathognomonic findings are defined in the histopathology of IMH, commonly described histologic findings can help distinguish IMH from autoimmune hepatitis or primary cholestatic liver diseases. Cholangiopathic phenotypes have been observed in the spectrum of IMH, which can be detected by first utilizing the R factor.

Once the diagnosis of IMH is made, management and treatment will depend on the overall CTCAE grade. Some patients, even those with grades 3–4 IMH, can exhibit spontaneous improvement without steroids upon ICI withdrawal. The goal of steroid treatment is biochemical remission with return of liver enzymes to baseline or normal values. Clinical observations suggest that lower doses of steroids compared to what is delineated in the current guidelines are effective while minimizing the risk of steroid-induced AE. The duration of corticosteroids is based on the trends of the liver enzymes, comorbidities, and prospects of being rechallenged with ICI while minimizing the risk of adverse events from steroids. Additional research is needed to establish the efficacy, the timing of initiation, and the selection of adjunctive treatments in IMH. Published clinical experience shows that not all patients who recover from grades 3–4 IMH experience recurrent IMH during ICI rechallenge. Therefore, the recommendation for permanent discontinuation of ICI in those categories should be revisited, particularly in cases where the patient’s cancer had responded well to ICI therapy and no good alternative treatment is available.

2 Gallbladder Injury

Very limited data are available regarding ICI-related cholecystitis. However, recognition and management of rare adverse events of ICI therapy are essential to maintain effective cancer treatment. Acute cholecystitis with or without cholangitis has been reported in case studies and case series [42, 84,85,86]. One study showed an incidence of 0.6% of acute acalculous cholecystitis, higher than the incidence (0.2%) among cancer patients without ICI exposure. The incidence is relatively higher in cases related to anti-CTLA-4 inhibitors [84]. The median time to cholecystitis was about 6 months after initiation of ICI therapy or after a median of four infusions of ICI. Traditional diagnostic tests and treatment strategies may be adopted from typical non-ICI-related cholecystitis. Management may include surgical cholecystectomy and percutaneous drainage, but the role of steroids is not yet defined [84]. Gallbladder wall perforation and sepsis have been reported with ICI-related cholecystitis [84]. To date, there is no study to document an association between patients who develop ICI-related gallbladder injury and those who develop ICI-mediated bile duct injury.

3 Pancreatic Toxicity

3.1 Incidence and Diagnosis

Among different ICI classes, the reported incidence of ICI-induced pancreatic injury is 0.6–4% [21, 87,88,89]. ICI-related clinical pancreatitis is therefore considered rare [21, 56]. A common scenario is asymptomatic elevations in serum lipase and amylase without clinically apparent pancreatitis. It is important to distinguish between asymptomatic ICI-related effects causing elevated serum lipase and amylase levels from those with clinically significant pancreatic injury in the form of true pancreatitis. Elevated lipase and amylase levels are generally an incidental finding detected during routine monitoring through expectations in the treatment protocol. Lipase and amylase elevations are usually recorded after a median of 3 months from ICI therapy initiation [90]. In cases of acute epigastric abdominal pain and nausea consistent with typical acute pancreatitis, toxicities involving other parts of the gastrointestinal tract, which could even coexist with pancreatic injury, must be ruled out. For example, choledocholithiasis must be excluded.

CTCAE version 5.0 offers a grading schema accounting for laboratory values, clinical signs, and symptoms (Table 2) [25].

Table 2 CTCAE (version 5.0) grading schema for lipase and amylase levels
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A retrospective study by Freeman-Keller et al. showed that 7 of 148 patients (4.7%) treated with nivolumab developed elevations in lipase/amylase of grades 1–3, of which 2 patients had grade 3 elevation [91]. The time to onset of these enzyme abnormalities was a median of 2 weeks after starting ICI therapy. A retrospective study at a cancer hospital of melanoma showed that 2 of 119 patients (1.7%) in the study were diagnosed with clinical pancreatitis but 52 patients (43.7%) had elevations in serum lipase and/or amylase (grades 3–4) without meeting diagnostic criteria for pancreatitis [92]. The pathophysiologic mechanism for asymptomatic elevations in these enzymes is currently unknown [92].

Initial investigation for both asymptomatic and symptomatic cases should include a close review of alcohol consumption behaviors, medication reconciliation to identify any pharmacologic agents that can predispose to pancreatitis, exclusion of hypertriglyceridemia, and cross-sectional imaging to evaluate for pancreatic lesions including metastasis of primary cancer. Traditional criteria for the diagnosis of acute interstitial pancreatitis include satisfying two of the following three features: compatible abdominal/gastrointestinal symptoms, serum lipase >3× ULN, and findings on cross-sectional imaging consistent with interstitial pancreatitis. Cross-sectional abdominal imaging with CT scan or MRI can help to establish the diagnosis of ICI-induced pancreatitis and to evaluate for short- and long-term adverse events of pancreatitis. Commonly observed features of ICI-induced pancreatitis are segmental hypoenhancement, peripancreatic fat stranding, and pancreatic enlargement with heterogeneous enhancement (Fig. 2). Because typical imaging features of interstitial pancreatitis could be observed in patients who are asymptomatic, it is reasonable to offer CT or MRI for additional workup. Some findings, such as pancreatic ductal dilation, may prompt further revaluation by endoscopic ultrasound. Autoimmune pancreatitis and IgG4-related pancreaticobiliary disease may manifest similarly and must be excluded.

Significant adverse consequences can occur in up to 10% of patients with ICI-induced pancreatitis. A case of severe pancreatitis with progressive morbid sequelae has also been reported [93]. One case report described a patient treated with nivolumab and ipilimumab who developed abdominal pain later diagnosed as pancreatic disease ascertained by PET-CT and endoscopic ultrasound, showing a diffusely lobular pancreas. This patient had concomitant distal common bile duct stricture associated with abnormal liver enzymes but no ANA or IgG4 elevation [94]. Exocrine pancreatic insufficiency (EPI) has also been observed as a sequela [95, 96]. In the context of ICI exposure, a retrospective study at a single-center cancer hospital revealed nine patients diagnosed with EPI (after a median time of 589 days after initiation of ICI) and received prescription for pancreatic enzyme replacement therapy [95]. Therefore, in patient presenting with new-onset diarrhea, the differential diagnosis may include EPI in addition to IMDC. A history of steatorrhea, combined with subsequent 24-h fecal fat testing and fecal elastase testing, would be informative.

The NCCN guidelines offer guidance for categorizing patients with asymptomatic pancreatic disease based on the levels of serum lipase and amylase and also for categorizing those with clinical symptomatic pancreatitis into mild (grade 1), moderate (grade 2), and severe disease (grades 3–4) [35]. Limited guidance is offered in the ASCO and SITC guidelines [22, 56, 101]. No recommendations are offered in the ESMO guidelines [55, 57].

Fig. 2
figure 2

(a) The peripancreatic fat stranding (short block arrows) are suggestive of pancreatitis. Pancreatic duct dilatation (long arrows) is due to metastasis in the pancreatic head. (b) The segmental hypoenhancement of pancreatic head and proximal pancreatic body (short block arrow) versus normal enhancement of distal pancreatic body and pancreatic tail (long arrow) is suggestive of acute pancreatitis. (Journal For Immunotherapy of Cancer 2019;Feb 6, 7(1):31)

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3.2 Management and Treatment Options

Given the similarities between symptomatic ICI-induced pancreatitis and “classic” acute pancreatitis, ICI-induced pancreatitis with clinical symptoms should be managed in a similar fashion to classic acute pancreatitis [97].

The unusual part of the diagnosis is related to the majority of patients who do not present with clinical symptoms. These patients may only have isolated elevations in serum lipase/amylase, and some patients, despite the lack of symptoms, could manifest in findings of pancreatitis on abdominal imaging. The optimal management of the asymptomatic case has not been systematically studied. Surveillance of pancreatic enzyme levels and the decision to continue ICI treatment is at the discretion of the clinician.

In patients who do present with typical symptoms of acute pancreatitis, ICI must be withheld, and the patient should be immediately evaluated in the emergency department with anticipation to be treated as a case of acute interstitial pancreatitis, which includes implementing initial nil per os status, administration of aggressive intravenous fluids such as lactated ringers within the first 24 h, and analgesic medication. Standard of care for acute pancreatitis should be followed.

The role of corticosteroids and other immunosuppressive agents in such patients is not well-established [22, 88]. The ASCO guidelines briefly suggest that asymptomatic disease may not warrant corticosteroid treatment [22]. In patients diagnosed with moderate or severe (grades 2–4) pancreatitis, NCCN guidelines recommend initiating oral prednisone or intravenous methylprednisolone at a dose of 0.5–1 mg/kg/day (for grade 2) or 1–2 mg/kg/day (for grades 3–4), with eventual taper of steroids over 4–6 weeks [35]. In the retrospective with 119 patient, ICI was withheld in 12.6% of patients, and 7.6% of patients were treated with oral steroids for lipase/amylase elevations without development of clinical pancreatitis [92].

Because serum lipase and amylase have no compelling clinical value in the management trajectory for acute pancreatitis, surveillance of these labs is not recommended. The patient should be assessed for signs of clinical improvement. Nonetheless, as with typical cases of acute pancreatitis, it remains important to monitor for development of morbid sequelae of clinical pancreatitis, especially in patients who are diagnosed with early-onset pancreatitis, as well as those with a history of smoking and hyperlipidemia, since these patients bear an increased risk of pancreatic injury [88, 98, 99]. Imaging abnormalities at the pancreas or pancreatic duct in some cases may warrant further characterization by endoscopic ultrasound. In patients who suffer from grades 1–2 symptomatic pancreatitis, the patient should discuss with the clinician about the prospects of resuming ICI treatment; ICI treatment should be permanently discontinued for those who suffered from grades 3–4 (severe) symptomatic pancreatitis [35].