A Call to End Routine Laboratory Monitoring for Patients on Isotretinoin

Clinicians who prescribe isotretinoin for acne or other skin conditions should stop blanket routine laboratory monitoring of liver function and lipids, given overwhelming evidence of an exceptionally low risk, researchers argued.

A careful medical history and selective symptom-based monitoring might lead to significant reductions in patient and provider anxiety and cost. Streamlined approaches to laboratory testing represented a “big step” in the right direction, but an even more selective approach is warranted, according to Joseph C. Pierson, MD, of the University of Vermont Health in Burlington, and colleagues in JAMA Dermatology.

“As we near a half-century since isotretinoin was first approved in the U.S., dermatologists have reflexively ordered laboratory monitoring for most of that time,” the authors wrote. “The streamlined protocols were a big step, but given [the evidence], we believe that testing can be further limited. We are not the first to propose this idea, but by combining updated evidence with context for why this matters and a rational framework to guide action, it is our hope that clinicians will gain confidence to take the next steps toward ending routine laboratory monitoring for isotretinoin.”

Future research should examine whether patient outcomes align with existing information, they added. If the data remain consistent, the cumulative evidence could inform refinement of guidelines for isotretinoin use.

Self-Protection Testing

Despite consistent evidence of a low risk of liver adverse effects or triglyceride-induced pancreatitis, most U.S. dermatologists probably still perform routine testing, said the senior author of one of the studies cited by Pierson and colleagues.

“I think the problem is that people think they’re testing in order to protect themselves from court cases,” Joerg Albrecht, MD, of Cook County Health in Chicago, told MedPage Today. “If the event never occurs, you’re never going to get a court case for it. If no one ever has a liver injury that has been documented, the likelihood that my patient is going to have it is similarly zero.”

Albrecht and colleagues performed a series of systematic literature reviews, which produced 125 articles that cumulatively showed an isotretinoin-linked adverse event risk of <1 in 10,000 patients. The few cases that were identified “were either idiosyncratic or not preventable by monitoring, accompanied by symptoms, or seen in identifiable predisposed individuals who might benefit from monitoring because of pre-existing conditions.”

“Basically, our conclusion was that no one has ever published or documented anywhere that anyone has ever had a serious liver injury from the drug,” he said.

Streamlining Not Enough

In their introduction, Pierson and colleagues acknowledged that dermatologists have moved away from routine repeat testing of alanine aminotransferase and triglyceride levels in patients treated with isotretinoin to testing at baseline and then once after the patient reached peak dose.

“But is routine laboratory testing even necessary for all patients?” they asked.

To address the question, they reviewed both current and historical evidence, beginning with the meta-analysis by Albrecht and colleagues. To examine the role of hepatic monitoring, Pierson and colleagues noted that the NIH LiverTox database assigned isotretinoin a drug-induced liver injury (DILI) likelihood score of D, indicative of “possible cause.” A number of other drugs have higher DILI likelihood scores but do not require routine laboratory monitoring.

The LiverTox database describes the evidence associated with a likelihood score of D as “single case reports … implicating the drug, but fewer than three cases have been reported in the literature, no characteristic signature has been identified, and the case reports may not have been very convincing.”

Other commonly used drugs in dermatology with a likelihood score of D include spironolactone, ivermectin, and acyclovir. On the other hand, terbinafine, minocycline, and acetaminophen have a likelihood score of A, denoting a drug “with a well-known and well-described history of causing DILI with a characteristic signature and more than 50 reported cases.” A symptom-based approach to liver function testing is recommended for those drugs.

“Notably, for the [FDA] to remove a drug from the market, its likelihood of DILI must be greater than 1 in 10,000 prescriptions gathered from a series of at least 30,000 patients,” wrote Pierson and co-authors. “While to our knowledge, a study has not been performed to assess DILI in patients receiving isotretinoin, that only a single case of liver injury has been possibly attributable to isotretinoin globally despite approximately 10 million patients receiving the treatment in the U.S. alone suggests that the likelihood of DILI attributed to isotretinoin is near zero.”

With regard to monitoring for triglyceride levels that could trigger pancreatitis, a systematic review identified only four cases among patients using isotretinoin, all of whom were older than 35. The study also suggested that the risk of idiosyncratic pancreatitis is higher than pancreatitis associated with hypertriglyceridemia.

What Next?

Given the evidence, Pierson and colleagues suggested a thorough screening of patients for risk factors for liver disease prior to prescribing isotretinoin. For patients without risk factors, a symptom-based approach to screening should be discussed with patients, along with counseling about stopping isotretinoin and seeking an evaluation if signs or symptoms occur.

With regard to triglycerides, American Heart Association/American College of Cardiology guidelines recommend a lipid panel for all patients between the ages of 9 and 11 years to screen for familial dyslipidemia, then every 5 years for patients older than 19.

“Thus, if patients have already undergone lipid screening with their practitioner, repeating this testing as part of routine laboratory monitoring is unnecessary and symptom-based monitoring can be adopted,” Pierson and colleagues suggested.

Albrecht noted that he remains skeptical that the evidence will persuade dermatologists to change their approach to lab tests for patients on isotretinoin.

“The problem I have is that you’re trying to protect yourself against an event that has never been described,” he said. “I don’t think someone who goes by that argumentation can be convinced of anything.”