How to Manage Immune Checkpoint Inhibitor Hepatotoxicity

Because liver toxicity can be a sign that these drugs are working, knowing how to manage this adverse event can help patients reap the full benefit, says Dr David Johnson.
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Hello. I'm Dr David Johnson, professor of medicine and chief of gastroenterology at Eastern Virginia medical School in Norfolk, Virginia.
Immune checkpoint inhibitors have dramatically contributed to oncologic success. This treatment represents a newer pathway in cancer therapy, effectively enhancing the immune response against tumor cells. Checkpoint inhibitors are increasingly utilized for dermatologic diseases like melanoma, non-small cell lung cancer, and - in the gastrointestinal world - for colorectal cancer with microsatellite instability.
These inhibitors block the immune checkpoint pathways, which normally regulate the immune responses that our body would intrinsically use to prevent harm from antigens and other immune-related damage. However, in selectively blocking this process, these agents can create tumor lysis.
This process also creates a risk for adverse events. This is something we've certainly seen in the treatment of checkpoint colitis. We're now seeing increasing reports of hepatotoxicity associated with these drugs.
Checkpoint inhibitor hepatotoxicity was the topic of a recent review article published in the journal Hepatology, for which I'll provide some highlights today.
Immune-Related Adverse Events
Depending on the drug used, the rate of immune-related adverse events may be as high as 85%, whereas for severe toxicities it's in the 20%-30% range. Liver toxicity is fairly common in patients receiving these treatments, occurring in up to 25%.
The pathophysiology underpinning immune-related adverse events occurs as a result of tumor lysis, which causes the release of numerous proteins and host antigens in a process called "epitope spreading." T-cell upregulation can then occur in any given target organ, which can result in an autoimmune response and a potentially inflammatory response.
In this discussion, we'll be focusing on immune-related adverse events occurring in the liver.
Hepatotoxicity Resulting From Checkpoint Inhibitors
The liver is very vulnerable to risk because it's constantly exposed to foreign antigens through portal venous blood flow. Immune tolerance to this nonpathogenic material is essential to avoid a state of constant inflammation. Hence, when we block this pathway, it potentially leads to an increased risk for hepatotoxicity.
When it comes to patient-specific risk for liver toxicity, the only clearly identified factor to date is whether a patient has had preexisting autoimmune disease. This makes sense, given that they're already upregulated. Metastatic disease to the liver doesn't seem to increase the risk.
The type of immune checkpoint inhibitor therapy may have an association with risk for immune-related hepatoxicity. There are a couple different classes of checkpoint inhibitors to consider, including CTLA-4 inhibitors such as ipilimumab, and anti-PD-1/PD-L1 drugs such as pembrolizumab, which is often used in melanoma therapy. However, the relative risk they pose for adverse events doesn't appear significant.
Making the Diagnosis
The diagnosis of checkpoint inhibitor-related hepatotoxicity is really a clinical one.
Hepatotoxicity resulting from the use of these agents ranges up to 28%. However, you need to be discriminant and put on your differential hat, because cancer progression is the most common cause of liver enzyme elevation in these patients.
Liver biopsy is rarely indicated, other than to look for exclusionary alternate causes. This requires you to differentiate between viral, drug, and immune-mediated causes of livery injury. Differentiation by liver histology is very challenging. This tends to uncover a panlobular or zone 3 type of liver inflammation, which is not necessarily in any way categoric for the diagnosis.
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