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Hepatic, pancreatic, and rare gastrointestinal complications of immune checkpoint inhibitor therapy

Hepatic, pancreatic, and rare gastrointestinal complications of immune checkpoint inhibitor therapy
Literature review current through: Jan 2024.
This topic last updated: Aug 19, 2022.

INTRODUCTION — With the widespread use of immune checkpoint inhibitors (ICI; also known as checkpoint inhibitor immunotherapy) for treatment of various types of cancer, immune-related adverse events (irAEs) are becoming increasingly common.

This topic will review the clinical manifestations, diagnosis, and management of hepatic, pancreatic, and rare gastrointestinal (GI) complications of ICIs in patients with cancer. The management of ICI colitis is discussed separately. The management of complications from ICIs involving other organ systems are also discussed separately.

(See "Immune checkpoint inhibitor colitis".)

(See "Toxicities associated with immune checkpoint inhibitors".)

(See "Cutaneous immune-related adverse events associated with immune checkpoint inhibitors".)

HEPATOTOXICITY

Epidemiology — Hepatic toxicity is a frequent complication of immune checkpoint inhibitors (ICI) and has been observed in patients treated with cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and programmed cell death receptor 1 (PD-1)/programmed cell death ligand 1 (PD-L1) inhibitors, either as single agents or in combination.

Single-agent immunotherapy – The reported rates of elevations in serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels range from 3 to 9 percent in patients treated with CTLA-4 inhibitors [1,2], from 1.5 to 5 percent in those treated with PD-1 inhibitors [2-7], and 3 percent in patients treated with PD-L1 inhibitors [8]. In approximately 1 percent of patients, hepatotoxicity is severe (eg, grade 3 or grade 4 (table 1)).

Combination immunotherapy – The rates and severity of hepatotoxicity both increase when CTLA-4 and PD-1 inhibitors are used in combination, with liver enzyme elevations occurring in 15 to 20 percent, and grade 3 or higher liver injury occurring in 4 to 9 percent of patients [2,9-11].

Clinical manifestations — Most patients who develop ICI hepatotoxicity present with a hepatocellular pattern of liver injury consisting of asymptomatic elevations in serum ALT and AST that are identified on routine monitoring. Although less common, a cholestatic (ie, elevated alkaline phosphatase and/or total bilirubin) or mixed pattern of injury has been reported [12-14]. While most patients are asymptomatic, some may occasionally present with fever, fatigue, and/or jaundice.

Elevations in liver enzymes typically occur 8 to 12 weeks after initiation of treatment. However, liver enzyme elevations have been reported as early as eight days after treatment is commenced or as late as several months after therapy is completed [15].

Diagnostic evaluation — ICI hepatotoxicity should be suspected in patients treated with immunotherapy who present with newly abnormal liver function tests, either with or without associated symptoms.

Differential diagnosis — The diagnosis of ICI hepatotoxicity is confirmed clinically by history and physical exam and by excluding other causes of abnormal liver tests during the diagnostic evaluation. The differential diagnosis is broad and can include infectious (eg, viral hepatitis) and noninfectious etiologies (eg, hepatic metastases, biliary obstruction, alcohol use, or drug-induced liver injury from an alternative agent).

History — Clinicians should ask about systemic symptoms, such as fever, malaise, and arthralgias, and obstructive symptoms such as abdominal pain, jaundice, and pruritus. The history should also aim to exclude other causes of liver injury, as follows (see "Approach to the patient with abnormal liver biochemical and function tests", section on 'History'):

A prior history of underlying liver conditions should be elicited. (See "Overview of the evaluation of hepatomegaly in adults", section on 'Causes'.)

Alcohol consumption should be quantified.

All medications (prescription, over the counter [eg, acetaminophen], complementary and alternative medications, and herbal supplements) should be carefully reviewed for potential hepatotoxicity.

Physical exam — The physical exam should include a focused evaluation of the abdomen, based on the history and reported symptoms. (See "Evaluation of the adult with abdominal pain", section on 'Diagnostic approach to acute abdominal pain'.)

The liver and the spleen should be palpated for size and consistency. Clinicians should also evaluate for the presence of jaundice or scleral icterus. ICI-mediated hepatitis typically occurs acutely, so signs suggestive of chronic liver disease (such as ascites or other stigmata of liver disease) may indicate an alternative etiology. (See "Approach to the patient with abnormal liver biochemical and function tests", section on 'Physical examination'.)

Laboratory evaluation — All patients with a hepatocellular liver injury pattern (elevated serum AST and ALT), particularly in the setting of systemic symptoms and/or jaundice, should undergo the following serologic evaluation to exclude acute or reactivation of viral hepatitis:

Hepatitis A (immunoglobulin M [IgM] anti-hepatitis A virus)

Hepatitis B (hepatitis B surface antigen [HBsAg], IgM anti-hepatitis B core antigen [anti-HBc], antibody to HbsAg)

Hepatitis C (anti-hepatitis C virus antibody [HCV], hepatitis C viral ribosomal ribonucleic acid [RNA])

Depending on the clinical circumstances, patients may also be tested for other infectious causes, such as hepatitis E, Epstein-Barr (EBV) virus, and/or cytomegalovirus (CMV).

Other laboratory testing that can be obtained to exclude non-infectious etiologies include 5'-nucleotidase for patients with an isolated elevated alkaline phosphatase; and creatinine kinase (CK) if myositis or muscle injury is suspected. Further details on the indications and specific laboratory testing for patients with abnormal aminotransferases are discussed separately. (See "Approach to the patient with abnormal liver biochemical and function tests", section on 'Evaluation of markedly elevated aminotransferases' and "Enzymatic measures of hepatic cholestasis (alkaline phosphatase, 5'-nucleotidase, gamma-glutamyl transpeptidase)".)

We do not routinely obtain serologies for autoimmune disease. Although some guidelines suggest obtaining antinuclear, antismooth muscle, antimitochondrial antibodies, and immunoglobulin G (IgG) levels, low titers of these autoimmune antibodies are prevalent in many chronic liver diseases. Moreover, their presence in the serum does not appreciably change management of ICI hepatotoxicity and their clinical significance in patients on ICI therapy is unclear.

Abdominal imaging — We obtain cross-sectional abdominal imaging to exclude other potential etiologies based on the pattern of the abnormal liver biochemical testing. In patients with ICI hepatotoxicity, imaging findings are typically nonspecific and include mild hepatomegaly, attenuated liver parenchyma, periportal edema, and/or periportal lymphadenopathy [16].

For patients with elevations in serum ALT and/or AST who have not had a recent computed tomography (CT) scan (eg, within the past four weeks) we obtain CT abdomen with contrast to assess for liver metastases. In patients with impaired kidney function, magnetic resonance imaging (MRI) of the liver with gadolinium contrast or abdominal ultrasound are alternative imaging modalities.

For patients who demonstrate a cholestatic pattern of liver injury (elevated alkaline phosphatase and/or total bilirubin), options to assess for bile duct obstruction include abdominal ultrasound, magnetic resonance cholangiopancreatography (MRCP), or CT abdomen with contrast.

Endoscopic retrograde cholangiopancreatography (ERCP) is not routinely performed to evaluate for suspected ICI hepatotoxicity in patients with a cholestatic pattern of injury. However, ERCP is warranted if initial imaging demonstrates a specific indication for this procedure, such as malignant biliary obstruction, choledocholithiasis, or acute cholangitis. (See "Overview of endoscopic retrograde cholangiopancreatography (ERCP) in adults", section on 'Indications'.)

What is the role of liver biopsy? — The role of liver biopsy in the diagnosis of patients with ICI hepatitis is controversial, and clinical practice is variable and based on institutional expertise. Our general approach is to initiate empiric treatment for ICI hepatotoxicity with glucocorticoids in most patients with a hepatocellular pattern of liver injury who have no other identifiable causes of liver disease. We reserve liver biopsy for the following situations:

Patients who fail to respond to initial immunosuppressive therapy (ie, glucocorticoids) for ICI hepatotoxicity. (See 'Refractory hepatotoxicity' below.)

Patients whose diagnosis remains unclear despite a thorough evaluation. For example, some patients may exhibit a predominantly cholestatic pattern of liver injury (ie, elevated alkaline phosphatase and/or total bilirubin) with no identifiable cause, such as biliary obstruction on imaging studies; this could indicate a rare alternative diagnosis to ICI hepatotoxicity, such as an infiltrating malignancy [13].

Some, but not all, UpToDate experts offer a liver biopsy prior to starting glucocorticoids in patients with grade 3 or 4 hepatotoxicity who hope to restart ICI therapy upon resolution of hepatotoxicity, due to limited alternative cancer treatment options. The purpose of the liver biopsy is to evaluate for rare alternative diagnoses (eg, infiltrating malignancy), which could alter the decision to restart ICIs. Clinicians should also offer such patients a risk-benefit discussion on the potential complications of liver biopsy [13]. (See 'Grade 3 or 4 hepatotoxicity' below.)

Our approach to liver biopsy is generally consistent with guidance from the American Society of Clinical Oncology (ASCO), but it differs from other guidelines. For example, the European Society of Medical Oncology (ESMO) advises liver biopsy in patients with "more severe hepatic reactions" [17], while the American Gastroenterological Association (AGA) suggests that a liver biopsy should be considered in patients with grade ≥2 hepatotoxicity who may require systemic glucocorticoids or potential discontinuation of ICIs [18].

It is unclear if liver biopsy can reliably distinguish ICI hepatotoxicity from other causes of drug-induced liver injury since the histologic changes associated with ICI hepatotoxicity are generally nonspecific. However, a liver biopsy could potentially distinguish ICI hepatotoxicity from noninflammatory causes of liver injury, such as malignancy. The more common histologic findings of ICI hepatotoxicity include panlobular inflammation with milder portal involvement and, occasionally, fibrin ring granuloma [13,19]. A primary biliary injury pattern with mild portal mononuclear infiltrate around proliferated bile ductules also has been reported [12,20].

There are limited data on the utility of liver biopsy in patients with suspected ICI hepatitis. In one retrospective observational study of 213 patients treated with ICI therapy who developed a grade 3 or 4 liver injury, the 107 patients who underwent liver biopsy had a longer time to initiation of appropriate glucocorticoid therapy and did not exhibit faster resolution of hepatotoxicity [13]. Among the 107 patients who underwent liver biopsy, only 12 patients (eleven percent) were determined to not have ICI hepatitis; four had malignant biliary obstruction, four had liver injury from a contemporaneous drug, two had diffuse malignant infiltration, and two remained without a clear diagnosis. Patients without ICI hepatitis on biopsy were also more likely to present with elevated bilirubin levels. Life-threatening procedural complications occurred in two patients (2 percent), including splenic biopsy and hemothorax [13].

Pretreatment assessment and monitoring — Patients on ICI should be routinely monitored for liver test abnormalities. A baseline ALT, AST, alkaline phosphatase, and total bilirubin should be obtained prior to initiation of ICI therapy and prior to each infusion. Patients with elevated baseline liver tests should undergo evaluation for potential causes of liver injury prior to initiation of ICI therapy. (See 'Differential diagnosis' above.)

Prior to initiating any systemic cancer therapy, all patients should also undergo pretreatment screening for the hepatitis B virus (algorithm 1). Patients with chronic hepatitis B receiving any systemic cancer therapy (including ICIs) should receive antiviral prophylactic therapy during and for at least one year after cancer therapy [21]. Although ICI therapy does not appear to have an adverse effect on underlying viral infection [22], undetected chronic hepatitis B can also complicate immunosuppression administered for the management of immune-related adverse events (irAEs). Such immunosuppressive agents can trigger reactivation of hepatitis B and result in serious liver injury and delayed cancer treatment. (See "Chemotherapy hepatotoxicity and dose modification in patients with liver disease: Conventional cytotoxic agents", section on 'HBV screening and management'.)

Management — The management of ICI hepatotoxicity depends on the severity of the hepatobiliary injury, based on the Common Terminology Criteria for Adverse Events (CTCAE) grade severity (table 1). Treatment generally involves the administration of systemic glucocorticoids. Other immunosuppressive agents (eg, mycophenolate mofetil, calcineurin inhibitors) typically are reserved for patients with glucocorticoid-refractory ICI hepatotoxicity.

Initial therapy — Our approach to the initial management of ICI hepatotoxicity is based upon the severity of the liver injury, as defined by CTCAE (table 1).

Grade 1 hepatotoxicity — ICI therapy can be continued without interruption. We advise patients to temporarily hold hepatotoxic medications (eg, acetaminophen, statins if possible) and discontinue alcohol intake. Patients require laboratory monitoring of liver function tests (ALT, AST, alkaline phosphatase, total bilirubin) one to two times weekly to assess for worsening hepatotoxicity.

Grade 2 hepatotoxicity — In patients with grade 2 ICI hepatotoxicity, treatment with the ICI should be held and other hepatotoxic medications discontinued. Clinical practice varies for the administration of immunosuppression. Our approach is as follows:

For patients who received ICI therapy and have no other identifiable causes of liver disease, some UpToDate experts administer glucocorticoids such as prednisone 0.5 to 1 mg/kg per day or an equivalent agent. Liver function tests are generally monitored every three to four days.

Alternatively, other experts prefer a period of initial observation rather than immediate administration of glucocorticoids, especially for patients with pre-existing liver metastases and those who received an ICI in combination with other potentially hepatotoxic cancer medications (eg, chemotherapy, vascular endothelial growth factor receptor [VEGFR] inhibitors, and small molecule inhibitors). For the latter, one approach is to also hold the additional cancer therapy, perform imaging studies (if not already obtained) to assess for new or progressive liver metastases, and monitor liver function tests. (See 'Abdominal imaging' above.)

In patients whose hepatotoxicity do not improve to grade 1 or lower after three to five days despite these interventions and have no other identifiable cause of liver disease, ICI hepatotoxicity should be suspected, glucocorticoids initiated, and liver function tests monitored every three to four days. For patients whose diagnosis still remains unclear (eg, cholestatic pattern of injury without a clear cause), some, but not all, UpToDate experts also obtain a liver biopsy to assess for other rare causes of the hepatotoxicity (ie, infiltrating malignancy) before initiating glucocorticoids. (See 'What is the role of liver biopsy?' above.)

For patients who exhibit a biochemical response to glucocorticoids with a reduction in liver tests to grade 1 or lower, prednisone can be tapered (generally by 10 mg weekly) over four to six weeks.

Grade 3 or 4 hepatotoxicity — In patients with grade 3 or 4 ICI hepatotoxicity who present with a predominantly hepatocellular pattern of liver injury and no other identifiable cause, ICI therapy is held, other hepatotoxic medications are discontinued, and glucocorticoids should be initiated. Patients should also be referred to a hepatologist or gastroenterologist with expertise in ICI hepatitis. Select patients with an atypical presentation (eg, cholestatic pattern of injury without a clear etiology) may be evaluated for possible liver biopsy. (See 'What is the role of liver biopsy?' above.)

We administer methylprednisolone at a dose of 1 mg/kg per day or an equivalent agent. Although ASCO guidelines recommend methylprednisolone at a daily dose ranging between 1 to 2 mg/kg [23], limited data suggest that a higher dose of 2 mg/kg does not reduce the likelihood of developing steroid refractory hepatotoxicity, does not shorten the time to resolution of hepatotoxicity, and is associated with a higher risk of steroid-related complications, when compared with the lower 1 mg/kg dose [24].

Liver tests and a basic metabolic panel with serum glucose should be monitored every one to two days in patients with grade 3 hepatotoxicity, and daily in patients with grade 4 hepatotoxicity. While close inpatient monitoring has been recommended for patients with AST/ALT >8 times the upper limit of normal (ULN) and/or a total bilirubin >3 times ULN [23], it is unclear if this is necessary in all patients as symptoms are typically mild and hospitalization has not been shown to improve outcomes.

In patients who exhibit a biochemical response to glucocorticoids with a reduction in liver tests to grade 1 or lower, the dose of methylprednisolone can be converted to an equivalent dose of oral glucocorticoid such as prednisone, which can then be tapered (generally by 10 to 20 mg weekly over six to ten weeks, although the optimal tapering duration is unclear). Glucocorticoids can be re-escalated if liver function tests worsen during the tapering period.

Refractory hepatotoxicity — Patients who are treated with glucocorticoids but have minimal improvement in liver tests after three to seven days of treatment are considered to have glucocorticoid-refractory ICI hepatotoxicity. Such patients should be evaluated for other etiologies of the hepatotoxicity and possible liver biopsy. (See 'Differential diagnosis' above and 'What is the role of liver biopsy?' above.)

Mycophenolate mofetil – For patients with glucocorticoid-refractory ICI hepatotoxicity, we administer mycophenolate mofetil (initial dose 500 mg twice daily to a maximum of 1.5 g twice daily) concurrently with glucocorticoids. While some guidelines recommend azathioprine in patients with glucocorticoid refractory ICI hepatotoxicity [23], we prefer mycophenolate mofetil due to its generally better tolerability and faster onset of action [25-29]. We obtain a complete blood count at least weekly to monitor for myelosuppression since both mycophenolate and azathioprine can lower blood cell counts. In an observational study of 21 patients with glucocorticoid-refractory ICI hepatitis, the addition of further immunosuppression (typically mycophenolate mofetil) prompted a more rapid decrease in ALT than glucocorticoids alone and was well-tolerated [29]. Similar results were seen in other case reports of ICI hepatitis where liver function tests improved within two weeks of initiating mycophenolate mofetil [26,27]. In contrast, although azathioprine has been used successfully to treat glucocorticoid refractory hepatotoxicity [25], the peak response to treatment is usually seen 30 days or more after treatment initiation.

Tacrolimus – In the rare circumstance when ICI hepatotoxicity is unresponsive to glucocorticoids and mycophenolate mofetil, or when mycophenolate is poorly tolerated, we add tacrolimus, a calcineurin inhibitor.

We typically start tacrolimus at 1 to 2 mg every 12 hours, based on the patient's baseline kidney function and weight; a lower initial dose is used in patients with kidney dysfunction while a higher initial dose may be chosen in patients with obesity. Tacrolimus is then increased to target the lowest dose that results in biochemical improvement in liver function tests.

Renal function tests should be checked weekly due to the risk of calcineurin nephrotoxicity. While we also obtain tacrolimus trough levels to monitor for toxicity and typically do not exceed a trough level of 8 to 10 ng/mL, tacrolimus dose adjustments are generally guided by liver function test response rather than tacrolimus trough levels.

Other agents – Other agents that have been used in patients with fulminant hepatis include antithymocyte globulin therapy [30], azathioprine [31], budesonide [32], and tocilizumab [33,34].

The use of infliximab is limited since this agent is ineffective for ICI hepatitis and is associated with a risk of hepatotoxicity. However, we have successfully administered infliximab in patients with both ICI hepatotoxicity and severe ICI colitis. (See "Immune checkpoint inhibitor colitis", section on 'Subsequent management (biologic agents)'.)

Once liver enzymes improve to grade 1 or less, a glucocorticoid taper can be initiated. The dose of methylprednisone is converted to an equivalent dose of oral glucocorticoid, such as prednisone. Tapering should be performed gradually, with a reduction in prednisone dose by 5 to 10 mg per week and with re-escalation of the glucocorticoid dose as needed based on liver biochemistries. In patients receiving concurrent mycophenolate mofetil and/or tacrolimus, these agents should be tapered gradually one at a time, once glucocorticoids have been successfully discontinued.

Resuming immunotherapy after prior toxicity — For patients whose ICI hepatotoxicity resolves, most will have liver function tests that return to baseline, since data suggest that ICI hepatotoxicity is not associated with chronic hepatitis [35]. As such, some patients may be eligible to restart ICI therapy. The approach to resuming ICI therapy is based upon the severity of the initial ICI hepatotoxicity (table 1), the ability to taper glucocorticoids or other immunosuppressive therapy, and whether ICI therapy was combined with other systemic cancer agents.

Prior grade 2 hepatotoxicity — Treatment with ICI therapy can be resumed when liver tests improve to grade 1 or less and glucocorticoids (if required) have been tapered to a dose of prednisone ≤10 mg daily or its equivalent.

Prior grade 3 or 4 hepatotoxicity — The decision to resume immunotherapy requires balancing the risks of recurrent adverse events against the responsiveness of the malignancy to ICI, the availability of effective alternative antineoplastic agents, and whether ICI therapy was used alone or in combination with other antineoplastic agents. (See "Toxicities associated with immune checkpoint inhibitors", section on 'Retreatment after prior toxicity'.)

Toxicity from ICI alone — For patients with prior grade 3 or 4 ICI hepatotoxicity on an ICI regimen that contained a CTLA-4 inhibitor (eg, ipilimumab) who are tapered to a glucocorticoid dose of prednisone ≤10 mg daily or its equivalent, we prefer to rechallenge with single-agent immunotherapy (ie, a PD-1 or PD-L1 inhibitor) rather than the original immunotherapy regimen. Most patients who previously received a single-agent PD-1 or PD-L1 inhibitor and plan to restart immunotherapy can also be safely rechallenged, either with their original agent or a different PD-1 or PD-L1 inhibitor.

Although the ASCO guidelines recommend permanent discontinuation of ICIs following symptomatic grade 3 or 4 hepatic toxicity [23], immunotherapy has been successfully resumed in selected patients. As an example, in a retrospective cohort study of patients with melanoma who previously developed a grade 3 or 4 ICI hepatotoxicity and were rechallenged with immunotherapy, only 13 percent (4 of 31 patients) developed recurrent (grade 2 or greater) hepatotoxicity, all of whom responded to resumed glucocorticoid therapy [36]. Additionally, while approximately one-half of the patients who restarted immunotherapy developed an irAE, most of these were mild and only 19 percent required treatment discontinuation. Patients who resumed ICI therapy were less likely to be rechallenged with their original ICI and more likely to receive single agent PD-1 or PD-L1 inhibitors rather than ipilimumab.

Toxicity from immunotherapy in combination with other agents — The concurrent or sequential use of immunotherapy with chemotherapy or other targeted agents (eg, VEGFR inhibitors, small molecule inhibitors) presents challenges for managing ICI hepatotoxicity. Although most combination regimens have toxicity profiles that are similar to those of each agent administered alone [37], data suggest an increased incidence of some grade ≥3 treatment-related adverse events, including hepatotoxicity, from the addition of ICIs to either chemotherapy or VEGFR inhibitors (eg, pembrolizumab plus axitinib in renal cell carcinoma) [38,39].

For patients with grade 3 or 4 hepatotoxicity on ICI in combination with other cancer therapy, the decision to restart therapy is based upon the inciting agent. If the hepatotoxicity is attributed to an etiology other than ICIs, then patients may be eligible to restart the prior ICI therapy along with appropriate management for the causative agent. However, if the hepatotoxicity is due to the ICI or is unclear, then referral to appropriate specialists (a multidisciplinary team with expertise in ICI toxicity including hepatology and medical oncology) is warranted to determine if one or both agents can be safely restarted [39].

PANCREATIC TOXICITIES

Exocrine pancreas — Immune checkpoint inhibitors (ICIs) can affect the exocrine pancreas and cause various conditions ranging from asymptomatic hyperlipasemia to acute pancreatitis and pancreatic exocrine deficiency.

Asymptomatic hyperlipasemia and acute pancreatitis

Epidemiology — In patients treated with ICI therapy, the incidence of asymptomatic hyperlipasemia (ie, elevations in lipase without associated symptoms) is approximately three to four percent [40-42], and can increase with longer duration of therapy (up to 16 percent [43]). In one study, elevations in lipase were more common in patients on CTLA-4 inhibitors (four percent) than in those treated with programmed cell death receptor 1 (PD-1) or programmed cell death ligand 1 (PD-L1) inhibitors (one percent), and were the most frequent in patients treated with combination immunotherapy (14 percent) [41].

Both acute symptomatic and asymptomatic pancreatitis (ie, asymptomatic patients with pancreatitis identified on imaging studies and lipase greater than three times the upper limit of normal [ULN]) are rare, with an incidence of approximately one percent or less [42].

Clinical manifestations — Most patients with lipase elevations on ICI therapy are asymptomatic, and the abnormality is typically identified during routine bloodwork. Lipase elevations can occur at any time throughout the treatment course and there is no clear temporal relationship to treatment initiation [41].

For the rare patients with symptomatic pancreatitis, the most common symptoms include fever, epigastric pain, nausea, vomiting, and diarrhea. These symptoms are similar to those seen with pancreatitis from other causes. Long-term complications have also been reported, including chronic pancreatitis, recurrent acute pancreatitis, exocrine pancreatic insufficiency, and diabetes mellitus [42]. (See "Clinical manifestations and diagnosis of acute pancreatitis".)

Patients with symptomatic disease present with higher lipase elevations overall and are more likely to receive treatment [42]. It is unknown whether asymptomatic and symptomatic lipase elevations represent a continuum of the same disease or are distinct pathophysiologic entities.

Differential diagnosis — Alternative etiologies for pancreatitis should be considered in all patients presenting with pancreatitis on ICI therapy, including alcohol-induced pancreatitis, gallstone pancreatitis, other medications and supplements, and complications from the underlying malignancy. In addition, patients should be evaluated for other causes of abdominal pain, nausea, and vomiting given the higher rates of mucosal gastrointestinal (GI) toxicities in patients on ICI therapy. These include duodenitis and gastritis, as well as bowel obstructions.

Diagnostic evaluation

Laboratory testing – We do not recommend routine testing of lipase or amylase in asymptomatic patients on ICI therapy. However, lipase should be ordered for patients on ICI therapy who present with new abdominal pain, nausea, and/or vomiting.

Abdominal imaging – CT using a pancreatic protocol should be performed in any patient on ICI therapy with typical symptoms of pancreatitis and an elevated lipase. In appropriate clinical settings, an ultrasound of the gallbladder may be useful in excluding cholelithiasis.

Management

Patients with hyperlipasemia alone – We typically observe patients with asymptomatic hyperlipasemia. We do not treat with glucocorticoids or other immunosuppressive medications, as there is no established benefit for therapy and no known long-term consequences of asymptomatic lipase elevation. Patients should also continue immunotherapy. Evidence to support following lipase levels are lacking. We therefore do not routinely monitor lipase levels unless patients develop symptoms of pancreatitis. (See 'Clinical manifestations' above.)

Patients with acute pancreatitis – In the absence of other clear etiologies identified on an initial workup, patients with acute pancreatitis on ICI therapy should be managed using a similar treatment approach to those with acute pancreatitis due to other causes, including supportive care such as intravenous (IV) fluids, bowel rest, and nutritional support as indicated. (See "Management of acute pancreatitis".)

We reserve the use of systemic glucocorticoids for patients who have severe pancreatitis or who do not improve rapidly with supportive care. We administer systemic glucocorticoids (prednisone 0.5 to 1 mg/kg twice a day or equivalent) for patients requiring hospitalization for suspected pancreatitis from ICI therapy, or for those whose symptoms do not begin to improve within 24 hours on a clear liquid diet. However, the efficacy of glucocorticoids is unknown, as retrospective studies have not demonstrated a clinical benefit with this approach [42].

Pancreatic exocrine insufficiency — Pancreatic exocrine insufficiency has been reported as a rare cause of diarrhea in patients on ICI therapy [44,45]. This diagnosis should be considered in any ICI therapy patient with new onset diarrhea who does not have evidence of inflammation in the colon or upper GI tract.

Although the relationship between pancreatic exocrine insufficiency and asymptomatic elevations in lipase is unknown, it may be a consequence of otherwise asymptomatic pancreatic inflammation. We have observed patients treated with ICI therapy who rapidly progress from symptomatic pancreatitis to pancreatic exocrine insufficiency; these patients respond to lipase replacement therapy. However, we do not offer immunosuppressive therapy since it is unclear whether rescue of exocrine function is possible after lipase deficiency becomes clinically evident. In addition, immunosuppression increases the risk of other complications, such as infection and cancer progression, in this already high-risk population [44,45].

Endocrine pancreas (diabetes mellitus) — ICIs can also affect the endocrine pancreas and result in type 1 diabetes mellitus. This topic is discussed separately. (See "Toxicities associated with immune checkpoint inhibitors", section on 'Type 1 diabetes mellitus'.)

RARE GI TOXICITIES

Epidemiology and pathogenesis — Rare gastrointestinal (GI) toxicities related to immune checkpoint inhibitors (ICIs) have been observed. These include new onset (or newly symptomatic) celiac disease, esophagitis, motility disorders such as gastroparesis, and acute cholecystitis [46-51]. Such toxicities occur in less than 1 percent of patients on ICI treatment.

Because these toxicities occur infrequently, we lack a detailed understanding of the pathogenesis and associated risk factors. The underlying mechanisms are presumed to be similar to more common toxicities and related to T cell-driven immune responses. It is also unclear whether the cancer type or the specific immunotherapy regimen used influences the risk of such rare toxicities. These rare GI toxicities are also more likely to be diagnosed by clinical teams experienced in the diagnosis and management of immune-mediated adverse events (irAEs) [52].

Celiac disease — Celiac disease is an immune disorder triggered the dietary protein gluten. Most patients with celiac disease have mild gastrointestinal complaints. However, others can present with more severe symptoms including diarrhea, weight loss, nutrient and vitamin deficiencies, and anemia. Further details on the pathogenesis and clinical manifestations of celiac disease are discussed separately. (See "Epidemiology, pathogenesis, and clinical manifestations of celiac disease in adults".)

Celiac disease has been reported in patients treated with cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and programmed cell death receptor 1 (PD-1)/programmed cell death ligand 1 (PD-L1) inhibitors either as single agents or in combination [46]. Among patients treated with ICIs who develop new onset diarrhea, the incidence of enteritis in combination with an elevated tissue transglutaminase-immunoglobulin A antibodies (tTG-IgA), a sensitive and specific serum antibody assay for celiac disease, is approximately 1 percent. It is unknown whether this represents true new onset celiac disease, or if it is due to a worsening subclinical version of celiac disease caused by immunotherapy.

Treatment of patients with celiac disease from ICI therapy should first include a strict gluten-free diet. Although patients with ICI-mediated celiac disease present with the same acute symptoms as those with ICI-mediated colitis, including with grade ≥3 toxicity in some cases, most will respond to a gluten-free diet [46].

If initial dietary therapy is ineffective by itself, patients may be evaluated for the addition of immunosuppressive therapy with systemic glucocorticoids or with biologic therapies such as infliximab or vedolizumab, but these are generally not needed. Patients who develop celiac disease on ICI therapy typically do not need to discontinue immunotherapy [46].

In general, celiac disease is a chronic inflammatory disease that does not spontaneously remit. However, data are limited for whether the disease eventually resolves in patients who develop it after treatment with ICIs and receive appropriate interventions.

Esophagitis — Rare esophageal toxicities that are potentially associated with ICI therapy include esophagitis, esophageal stenosis, and esophagitis desiccans superficialis [48].

It is unclear whether esophagitis truly represent an irAE, since it has been demonstrated in some, but not all studies [47,49]. As an example, in one retrospective observational study of 657 patients who received ICI therapy and underwent an upper endoscopy for various indications, the frequency of visible esophagitis without a clear alternative explanation was approximately 3 percent [47]. Histology mostly demonstrated nonspecific findings such as neutrophilic and/or eosinophilic inflammation, although lymphocytic or plasmacytic infiltrates were noted in approximately one-half of all patients.

Data are limited for treatment of esophagitis after ICI therapy, and the optimal management has not been defined. In one study, most patients were successfully treated with proton pump inhibitors [47]. Others with ICI-induced inflammation elsewhere in the upper or lower GI tract who were treated with glucocorticoids or infliximab were noted to have concurrent resolution of esophagitis [53].

Gastroparesis and motility disorders — Motility disorders, in particular gastroparesis, are rarely reported but potentially overlooked complications of ICI therapy in the GI tract [50,54].

The true incidence of gastroparesis after ICI therapy is unknown as data are limited. In addition, the diagnosis may be overlooked since studies used to diagnose gastroparesis, such as gastric scintigraphy, are not part of the standard evaluation of patients with new GI irAEs. In one retrospective study, among nine patients treated with ICIs who underwent gastric scintigraphy for evaluation of new symptoms suggestive of gastroparesis, three had confirmed delayed gastric emptying [50].

The management of patients with gastroparesis after ICI therapy is the same as those with gastroparesis due to other causes. In one observational study, one of three patients with confirmed gastroparesis after ICI therapy was treated with a gastroparesis diet and metoclopramide with some improvement in symptoms, and none received glucocorticoids [50]. (See "Treatment of gastroparesis".)

Acute cholecystitis — Acute cholecystitis is a rare toxicity in patients treated with ICI therapy. In one case series of over 4000 patients treated with ICI therapy, the rate of acute cholecystitis was 0.6 percent, which was higher than that of a cancer-matched control cohort (0.2 percent) [51]. Whether these cases of acute cholecystitis truly represent an irAE is not clear, although patients with acute cholecystitis due to other causes were excluded from the analysis.

For patients with acute cholecystitis after ICI therapy, we discontinue immunotherapy and avoid the use of systemic glucocorticoids in the absence of a clear indication, due to the increased risk of infection. Otherwise, the management of these patients is the same as that used for those with acute cholecystitis due other causes. (See "Treatment of acute calculous cholecystitis".)

In one observational study, most patients received standard cholecystitis management including antibiotics and fluids [51]. Surgical cholecystectomy and percutaneous gallbladder drainage was performed in 20 and 32 percent of patients, respectively. A minority of patients (20 percent) receiving systemic glucocorticoids, but the efficacy of this treatment strategy was unclear. Nearly one-half of patients (40 percent) were able to restart immunotherapy.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Management of toxicities due to checkpoint inhibitor immunotherapy".)

SUMMARY AND RECOMMENDATIONS

Clinical presentation of ICI hepatotoxicity – Hepatotoxicity due to immune checkpoint inhibitor (ICI) therapy often presents as a hepatocellular pattern of liver injury consisting of asymptomatic elevations in serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) that are identified on routine monitoring. A cholestatic (ie, elevated alkaline phosphatase and/or total bilirubin) or mixed pattern of injury is less common. (See 'Clinical manifestations' above.)

Diagnostic evaluation of ICI hepatotoxicity The diagnosis is confirmed clinically by history and physical exam and by excluding other causes of abnormal liver function tests such as infection (eg, viral hepatitis) and noninfectious etiologies (eg, hepatic metastases, biliary obstruction, alcohol use, or drug-induced liver injury from an alternative agent). (See 'Differential diagnosis' above and 'Diagnostic evaluation' above.)

Laboratory evaluation – Serologic evaluation for hepatitis A, B, and C should be obtained to exclude acute or reactivation of viral hepatitis. Testing for hepatis E, Epstein-Barr (EBV) virus, and cytomegalovirus (CMV) may also be indicated. (See 'Laboratory evaluation' above.)

Other tests to exclude noninfectious etiologies include 5' nucleotidase for patients with an isolated alkaline phosphatase; and creatinine kinase (CK) if myositis or muscle damage is suspected. We do not routinely obtain serologies for autoimmune disease.

Imaging – For patients with elevations in serum ALT and/or AST who have not had a recent CT scan, we obtain CT abdomen with contrast to assess for liver metastases. In patients with impaired kidney function, MRI of the liver with gadolinium contrast or abdominal ultrasound are alternative imaging modalities. (See 'Abdominal imaging' above.)

For those who demonstrate a cholestatic pattern of liver injury (elevated alkaline phosphatase and/or total bilirubin), options to assess for bile duct obstruction include abdominal ultrasound, magnetic resonance cholangiopancreatography (MRCP), or CT abdomen with contrast.

Is there a role for liver biopsy? – The role of liver biopsy is controversial, and clinical practice is variable and based on institutional expertise. (See 'What is the role of liver biopsy?' above.)

-Our general practice is to initiate empiric treatment for ICI hepatotoxicity with glucocorticoids in most patients with a hepatocellular pattern of liver injury who have no other identifiable causes of liver injury.

-We reserve liver biopsy for patients who fail to respond to initial immunosuppressive therapy and/or those whose diagnosis remains unclear despite a thorough evaluation (eg, a cholestatic pattern of liver injury with no identifiable cause).

Management of ICI hepatotoxicity – Management is based on disease severity, as defined by Common Terminology Criteria for Adverse Events (CTCAE) grading for hepatobiliary toxicity (table 1). (See 'Management' above.)

Grade 1 – Continue ICI therapy. Hold hepatotoxic medications temporarily, if possible. Monitor liver function tests one to two times weekly. (See 'Grade 1 hepatotoxicity' above.)

Grade 2 or higher – For most patients with grade ≥2 or higher hepatotoxicity, we suggest initiation of systemic glucocorticoids (Grade 2C). Specific details regarding our stepwise approach are as follows:

-Grade 2 – Hold ICI therapy and discontinue other hepatotoxic medications. For patients who received ICI therapy alone and have no other identifiable causes of liver disease, some UpToDate experts administer glucocorticoids such as prednisone 0.5 to 1 mg/kg/day or an equivalent agent and monitor liver function tests every three to four days. Alternatively, other experts prefer a period of initial observation rather than immediate administration of glucocorticoids, especially for patients with pre-existing liver metastases and those who received an ICI in combination with other potentially hepatotoxic cancer medications. (See 'Grade 2 hepatotoxicity' above.)

-Grade 3 or 4 – Hold ICI therapy and discontinue other hepatotoxic medications. For patients with a predominantly hepatocellular pattern of liver injury and no other identifiable cause, administer methylprednisolone at 1 mg/kg per day or an equivalent agent. Monitor liver tests and basic metabolic panel every one to two days for grade 3 hepatitis and daily for grade 4 hepatitis. Refer to a hepatologist or gastroenterologist with expertise in ICI hepatitis. (See 'Grade 3 or 4 hepatotoxicity' above.)

Refractory hepatotoxicity – For patients who do not respond to glucocorticoid therapy, we suggest the addition of mycophenolate mofetil rather than azathioprine to glucocorticoids (Grade 2C), due to better tolerability and faster onset of action. Tacrolimus is used for the rare patient who is unresponsive to both steroids and mycophenolate mofetil. The use of infliximab is limited since this agent is ineffective for ICI hepatitis and is associated with a risk of hepatotoxicity. (See 'Refractory hepatotoxicity' above.)

Resuming ICI therapy – The approach to resuming ICI therapy is based upon the severity of the initial ICI hepatotoxicity, the ability to taper glucocorticoids or other immunosuppressive therapy, and whether ICI therapy was combined with other systemic cancer agents. (See 'Resuming immunotherapy after prior toxicity' above.)

Pancreatic toxicities – The most common exocrine pancreatic toxicities associated with ICIs include asymptomatic hyperlipasemia (elevations in lipase) and acute pancreatitis. (See 'Pancreatic toxicities' above.)

Asymptomatic hyperlipasemia – We typically observe and do not treat with glucocorticoids or other immunosuppressive medications. (See 'Management' above.)

Acute pancreatitis – Patients should be managed using a similar treatment approach to those with acute pancreatitis due to other causes. We reserve the use of systemic glucocorticoids for patients who have severe pancreatitis or who do not improve rapidly with supportive care. (See 'Management' above.)

Rare GI toxicities – Rare GI toxicities related to ICIs include celiac disease, esophagitis, motility disorders such as gastroparesis, and acute cholecystitis. (See 'Rare GI toxicities' above.)

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References

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