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Putting muscle into isotretinoin laboratory testing isn’t chopped liver!

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By Danielle M. DeHoratius, MD
August 14, 2019
Vol. 1, No. 23

DeHoratiusWhen I first became interested in dermatology during medical school, I started shadowing dermatologists. When prescribing isotretinoin all the physicians needed was a small yellow sticker. They could give patients months of medication at a time. I am not certain what specific laboratory monitoring protocols were used, but I am sure it wasn’t what we perform today. How times have changed over the years.

In speaking to my colleagues there seems to be no standardization of what labs to order and when. The AAD’s recommendations are as follow: Routine monitoring of liver function tests, serum cholesterol, and triglycerides at baseline and again until response to treatment is established. (1) Routine monitoring of complete blood count is not recommended.

Opel et al established that in patients with normal baseline triglycerides there is little value in monitoring triglycerides during therapy (2). There is also low incidence of hypertriglyceride-associated pancreatitis. When pancreatitis does occur, it is more likely to be idiosyncratic.

Hansen et al. recently reported that in healthy patients with normal baseline lipid panel and liver function test results,DermNetNZ_edited repeated studies should be performed after 2 months of isotretinoin therapy (3). They concluded that although abnormalities in serum lipids were not infrequent, they were mild to moderate, and most common around the second month of treatment. If findings are normal, no further testing may be required. Routine complete blood cell count monitoring is not recommended. The authors report that given the low prevalence of clinically significant liver and lipid abnormalities, practitioners should examine their laboratory monitoring practices and consider adjustments to improve the patient experience and reduce the per capita cost of health care, while maintaining patient safety. Limitations of this study were that it was a non-controlled, single center study and the results may not be generalizable.  

The authors suggest that we could be over-monitoring our patients. But are we actually monitoring the appropriate lab values with isotretinoin? Webster et al performed a retrospective chart review in patients treated with isotretinoin for acne between 2005 and 2014. The tests obtained were CBC, lipid panel, AST, ALT, CK, GGT, and C-reactive protein as well as HCG in female patients. Tests that were abnormal were monitored until they normalized (4). AST and ALT are not liver-specific enzymes as they are found in the liver, muscle, and other tissues. GGT is a liver-specific enzyme and CK is a muscle-specific enzyme. In the study when AST was elevated it was often associated with CK elevation, suggesting that muscle was the source of the elevation. GGT was uncommonly elevated.

Lee et al confirmed that the incidence of liver abnormalities is low and measuring AST and ALT may not be cost effective (5). When the laboratory values are abnormal it is usually mild. Muscle tests were much more commonly elevated often with no symptoms present with the patients. This can often occur due to exercise, but we must keep rhabdomyolysis in the back of our minds.  Symptoms of rhabdomyolysis are muscle pain, fatigue, and weakness; this can lead to renal damage (6). There have been reports of severe rhabdomyolysis in patients taking isotretinoin. It may be prudent to counsel patients to avoid strenuous exercise during therapy. Perhaps it would be better to monitor the GGT to assess liver damage and CK for muscle alterations.

Most recently, Shah and Kroshinsky performed a retrospective analysis of patients’ diagnoses with acne vulgaris and treated with isotretinoin (7). In all 903 patients there was no clinically significant anemia, thrombocytopenia or leukopenia. Triglycerides were elevated in 197 subjects, mostly associated with obesity, increased baseline triglycerides levels, and medications. AST (N=102 and ALT (N=113) was also elevated individually in patients. Increase in both AST and ALT was found to in 7 patients and all were related to alcohol consumption. All elevations resolved at the completion of the medication.

What is your protocol for monitoring your isotretinoin patients? New data may alter your approach, if you haven’t changed already. 

Point to remember: We may be over-monitoring our isotretinoin patients. More research is needed to avoid unnecessary blood draws and excess use of  health care dollars.

Our expert’s viewpoint

Joslyn S. Kirby, MD

“I know that change is difficult, and comes slowly, and that it is the work of many days strung together in a long line until the origin of them is forgotten.” 
– Veronica Roth

It may have been the isotretinoin package insert from 1982 that informed my practice — which labs I was taught to check and to check labs monthly. This makes sense, the package insert is initially the best (and sometimes only) evidence we have to inform our practice. 

Over the years, more and more people were treated and this created a new opportunity — to question what we are doing and why. Lab monitoring is useful to detect a change that is not otherwise detectable, would change management, and could avoid harm. There has been less investigation of GGT and CK and the value of monitoring these tests during isotretinoin therapy. My thoughts are — if GGT or CK is elevated, what happens during the course of treatment? Does it normalize? How often is there harm? For the high school athlete on isotretinoin, who has a mildly elevated CK but is asymptomatic — would the elevation be there if we hadn’t looked? If it’s asymptomatic, what is the chance that it will result in harm? Perhaps the patient benefits from knowing when to call us — the signs of rhabdomyolysis — muscle pain, fatigue, and weakness so we can evaluate. Keeping in mind that rhabdomyolysis can have a favorable prognosis when treated and does not always result in kidney injury.

The Roth quote reminds me of a couple things — first, that ‘what we know’ in medicine is always changing and so my practice cannot depend on tradition, but needs to change. Secondly, she reminds me that making a change can be difficult, but change is begun by starting with just one change with one patient until that change is my ‘new normal.’

1. Zaenglein AL, Pathy AL, Schlosser BJ, Alikhan A, et al. Guidelines of care for the management of acne vulgaris. J Am Acad Dermatol. 2016 Feb 15. 
2. Opel D, Kramer ON, Chevalier M, Bigby M, Albrecht J. Not every patient needs a triglyceride check, but all can get pancreatitis: a systemic review and clinical characterization of isotretinoin-associated pancreatitis. Br J Dermatol. 2017 Pct;177(4):960-966. Epub 2017 Sep 19
3. Hansen TJ, Lucking AM, Miller JJ, Kirby JS, et al. Standardized laboratory monitoring with use of isotretinoin in acne. J Am Acad Dermatol 2016;75:323-8.
4. Webster GF, Webster TG, Grimes LR. Laboratory tests in patients treated with isotretinoin : occurrence of liver and muscle abnormalities and failure of AST and ALT to predict liver abnormality. Dermatol Online J 2017;23:1-3. 
5. Lee YH, Scharnitz TP, Muscat J, Chen A, Gupta-Elera G, Kirby JS. Laboratory monitoring during isotretinoin therapy for acne. JAMA Dermatol. 2016;152(1):35-44.
6. Chroni E, Monastirli A, Tsambaos D. Neuromuscular adverse effects associated with systemic retinoid dermatotherapy. Drug Safety 22:25-34, 2010.
7. Shah R & Kroshinsky D. Re-evaluating the Need for Routine Laboratory Monitoring in Isotretinoin Patients: A Retrospective Analysis. J Am Acad Dermatol 2019 accepted manuscript

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