Monitoring specific values at baseline and throughout treatment is standard of care for isotretinoin therapy; however, creatine kinase (CK) blood monitoring is often excluded. Herein, we describe the importance of CK monitoring during isotretinoin therapy to assess the risk of rhabdomyolysis and potential renal damage, regardless of muscle-related symptom presentation. We present 2 patients with hyperCKemia: a 16-year-old male on isotretinoin whose CK levels were elevated (7,325 U/L) when rhabdomyolysis symptoms were present, and an asymptomatic 18-year-old male with elevated CK levels (35,000 U/L) before starting isotretinoin. Based on our experience, we strongly recommend obtaining CK levels to monitor for and potentially prevent rhabdomyolysis and its associated complications.

  • A common finding in isotretinoin patients is hyperCKemia or elevated creatine kinase (CK) levels.

  • CK levels are only measured if indicated by patients’ risk factors and are not routinely ordered. However, studies show that approximately 16–51% of patients on isotretinoin develop hyperCKemia during the course of treatment.

  • HyperCKemia with or without muscle-related complaints in isotretinoin-treated patients has been described as benign phenomenon.

  • Majority of those who take isotretinoin are in high school and a significant number will play high school sports.

  • Isotretinoin has been associated with hyperCKemia which increases the risk of rhabdomyolysis and acute kidney injury, a medical emergency, which warrants the importance of creatine kinase routine monitoring.

  • Physicians should consider baseline and routine monitoring in patients, particularly since asymptomatic cases of hyperCKemia delays the warning signs of a medical emergency.

  • Physicians should counsel patients (particularly those with a history of heavy/vigorous exercise) on physical activity in moderation, hydration, and nutritional supplement usage because of the potential risk for rhabdomyolysis.

Isotretinoin (13-cis-retinoic acid) treats acne vulgaris refractory to other treatment modalities. Dosing is weight-based and requires a total cumulative dose of 120–150 mg/kg; on average, it takes 15–20 weeks of treatment to clear severe acne and reduce the risk of relapse. Isotretinoin is associated with various side effects, including dry skin and mucous membranes, cheilitis, hypertriglyceridemia, liver enzyme abnormalities, hematuria, leukopenia, and teratogenicity [1]. Laboratory studies used to identify high-risk patients for isotretinoin-related complications include a fasting complete blood count (CBC), comprehensive metabolic panel (CMP), lipid panel, and, in females, a pregnancy test [1, 2].

A less characterized but common finding in isotretinoin patients is hyperCKemia or elevated creatine kinase (CK) levels [3]. CK elevations have been described as a benign finding in isotretinoin patients; however, CK levels greater than 1,000 U/L are concerning for rhabdomyolysis [3]. Rhabdomyolysis is a medical emergency and can be fatal due to its association with acute kidney injury (AKI), electrolyte abnormalities, and acid-base disorders [4]. The risk of AKI in rhabdomyolysis is low for CK levels less than 15,000–20,000 U/L; however, coexisting conditions such as dehydration puts patients with lower CK values at risk for AKI [5].

Rhabdomyolysis involves the breakdown of skeletal muscle, caused by either traumatic or nontraumatic muscular injury (e.g., drugs, alcohol, and seizures). This leads to the release of toxic intracellular products, like myoglobin, into the bloodstream and electrolyte abnormalities [6]. Rhabdomyolysis can present with myalgias, arthralgias, generalized weakness, and pigmenturia [7, 8]. Patients can be asymptomatic; therefore, symptom-based screening is not always reliable [7, 9, 10]. Diagnosis is supported by laboratory studies such as CK, CBC (leukocytosis), urinalysis (e.g., hematuria and myoglobinuria), and serum electrolytes (e.g., hyperkalemia, hyperphosphatemia, and hypocalcemia) [7, 8]. There is no defined cutoff value for CK elevation in the setting of rhabdomyolysis, thus CK levels are interpreted in the context of the clinical scenario [8].

Notably, isotretinoin has been theorized to cause oxidative stress in muscles and reported to cause rhabdomyolysis [11]. Despite reports in the literature for rhabdomyolysis and its complications in patients on isotretinoin (Table 1) [4, 12-14], obtaining CK levels is not routinely performed unless indicated by muscle-related symptoms or other risk factors. Therefore, baseline screening and regular monitoring of CK levels should be considered in all patients beginning isotretinoin as a precautionary measure.

Table 1.

CK levels and clinical outcomes of rhabdomyolysis in patients taking isotretinoin for acne

CK levels and clinical outcomes of rhabdomyolysis in patients taking isotretinoin for acne
CK levels and clinical outcomes of rhabdomyolysis in patients taking isotretinoin for acne

Patient 1

A 16-year-old White-Hispanic male with no past medical history and weighing 68 kg presented to our office with severe nodulocystic acne. He had no notable improvement when treated with topical clindamycin gel, dapsone 7.5% gel, adapalene/benzoyl peroxide 0.3%/2.5% gel, adapalene 0.1% gel, azelaic acid 15% gel, tretinoin 0.1% cream, and doxycycline 100 mg daily. Since prior treatment failed, isotretinoin treatment was considered as his next logical step. His baseline lab orders included: CMP, CBC with differential, gamma-glutamyl transferase tests, amylase, lipase, and lipid panel. BUN and creatinine levels were elevated at baseline; CK levels were not taken. Due to the initial renal dysfunction, blood work was repeated, at which point the values normalized. The patient began isotretinoin with a starting dose of 20 mg (0.44 mg/kg/day), then 30 mg daily for 2 months, followed by his daily dose 70 mg (1 mg/kg/day). At month 5, the patient reported increased physical activity due to swimming and complained of bilateral leg pain. The patient was found to have a CK value of 7,325 U/L (normal range <245 U/L), AST value of 139 U/L (normal range 12–32 U/L) (Table 2). He was admitted to the emergency department and treated aggressively with intravenous fluids. The CK values recorded during the ER visit remained elevated but decreased over time (Table 2). The patient was discharged after 1 day and advised to drink plenty of fluids, avoid strenuous activity for the next 24 h, and discontinue isotretinoin until labs normalized. Once normalized, isotretinoin treatment resumed for 1 month at 40 mg daily but was discontinued again due to neutropenia: 1,680 (normal range 1,800–8,000 U/L).

Table 2.

Blood test findings of patient 1 at baseline and throughout isotretinoin treatment

Blood test findings of patient 1 at baseline and throughout isotretinoin treatment
Blood test findings of patient 1 at baseline and throughout isotretinoin treatment

Patient 2

An 18-year-old White-Hispanic male weighing 80 kg presented to our office with severe nodulocystic acne. Past medical history included onychomycosis, treated with terbinafine, and no previous surgeries. His initial acne treatment was topical clindamycin solution, azelaic acid 15% gel and tretinoin 0.1%, doxycycline 100 mg daily, and minocycline 100 mg daily, with no notable improvement. Prior to isotretinoin treatment, routine studies revealed incidental findings of AST 720 U/L, ALT 170 U/L (normal range 8–46 U/L), and CK 35,616 U/L. The patient was asymptomatic, denying any myalgia, arthralgia, muscle weakness, and abdominal tenderness. He was subsequently referred to the ER 48 h later for workup of exertional rhabdomyolysis and transaminitis, where repeat blood work demonstrated hyperCKemia and elevated liver transaminases (Table 3). Coagulation studies, gamma-glutamyl transferase, HbsAg, triglycerides, and liver ultrasound to rule out concomitant hepatic involvement were all normal. The patient reported a rigorous exercise regimen consisting of heavy weight lifting and consumption of pre-workout protein shakes. The patient was discharged and advised to increase water intake, refrain from high-intensity workouts until cleared by a primary care physician. Within a month, he started isotretinoin therapy at 20 mg daily.

Table 3.

Blood test findings of patient 2 at baseline and throughout isotretinoin treatment

Blood test findings of patient 2 at baseline and throughout isotretinoin treatment
Blood test findings of patient 2 at baseline and throughout isotretinoin treatment

Due to isotretinoin’s potential side effects, the standard of care is to monitor CBC, CMP, lipid panel, and pregnancy status. However, CK levels are not routinely measured unless warranted by symptoms or risk factors, despite recent studies demonstrating that 16–51% of patients on isotretinoin develop hyperCKemia during the course of treatment [3]. Although there have been rare reports of isotretinoin-induced rhabdomyolysis [4], the true incidence of this adverse effect is hard to determine as many cases may go unrecognized.

The key differences between the 2 cases presented were when CK levels were obtained and the presence of symptoms. For patient 1, CK levels were checked once rhabdomyolysis symptoms occurred while on isotretinoin. Whereas patient 2 had elevated CK levels at baseline and was asymptomatic, despite having rhabdomyolysis and CK levels with increased risk for AKI. Although it is important to measure CK levels in symptomatic patients, levels should also be checked before starting isotretinoin and regularly after that, even in the absence of symptoms. It is crucial to identify patients with elevated CK levels, since they may require specific interventions such as temporary discontinuation of the drug, dose reduction, increase in hydration, avoidance of muscle-building supplementation, reduction of strenuous exercise, and more frequent follow-up [4]. Patient 2 developed hyperCKemia and rhabdomyolysis before starting treatment; since isotretinoin is believed to cause oxidative stress within muscle tissue, we deferred treatment until the patient’s CK levels normalized. Since rhabdomyolysis may go unrecognized in asymptomatic individuals, we recommend obtaining monthly CK levels. Prompt recognition and treatment of patients with rhabdomyolysis can prevent AKI complications and improve prognosis [15]. If patients develop AKI due to rhabdomyolysis, we suggest monitoring BUN, creatinine, and CK levels before initiating/restarting treatment as there have been 5 case reports of isotretinoin-induced AKI in the forms of acute interstitial nephritis, nephrotic syndrome, and hematuria with dysuria. All of these cases endorsed the resolution of AKI with the cessation of isotretinoin and appropriate resuscitation and management [16-18]. Although retinoids have been shown to reduce damage and inflammation in experimental models of glomerulonephritis and renal interstitial disease, paradoxically, isotretinoin’s xerotic mucosal side effects have been described to cause hematuria [18].

One should assess patients for risk factors of rhabdomyolysis, which includes alcohol abuse, use of illicit drugs (e.g., cocaine), heavy exercise/muscle overexertion, trauma/crush injuries, and medications (e.g., statins and corticosteroids) [19]. Of note, a synergistic effect of isotretinoin and exercise on CK levels has been postulated, but there is not enough evidence to suggest avoiding isotretinoin in athletes [6, 11]. Considering the age-group in which isotretinoin is commonly prescribed, patients should also be educated on physical activity in moderation, maintaining hydration, and avoiding nutritional supplementation (especially those containing ephedra, caffeine, and creatine) because of the potential risk for rhabdomyolysis [20, 21].

As the clinical significance of hyperCKemia in isotretinoin patients remains obscure, further studies are necessary to determine the costs and benefits of obtaining CK levels at baseline and monthly throughout treatment. We believe it is best to err on the side of caution and recommend monitoring of CK levels at baseline and throughout therapy. Currently, there is no data on whether it is safe for patients with elevated CK levels or a history of rhabdomyolysis to take isotretinoin. Both patients proceeded to resume isotretinoin therapy. However, after 2 months, patient 1 developed transient neutropenia and subsequently discontinued treatment, whereas patient 2 had no further complications on a low dose.

In this article, we described the lack of monitoring CK levels in routine blood work ordered for isotretinoin patients despite the significance of hyperCKemia progressing to severe consequences and in some cases requiring hospitalization. HyperCKemia is an indicator of potential rhabdomyolysis and has been reported to progress to AKI in various instances. Both patients were diagnosed with rhabdomyolysis in the ER and assessed for potential AKI.

Current practices do not indicate hyperCKemia as a contraindication for isotretinoin. Further studies should be conducted to better elucidate this relationship, and to identify if there are any potential long-term consequences of chronically elevated CK levels. Studies on patients that developed hyperCKemia, rhabdomyolysis, or AKI on isotretinoin should also be analyzed. As more isotretinoin-associated hyperCKemia cases are reported, it is increasingly vital to advocate for routine monitoring of CK both at baseline and throughout treatment, as well as to educate patients on the importance of maintaining hydration and moderating strenuous physical activity.

We would like to thank Giselle Gutierrez, APRN, and Vitor Weinman, MD (Dr. Weinmann & Associates, Miami, FL, USA). We would also like to thank Ana Parades, MD (Department of Pediatric Nephrology, Nicklaus Children’s Hospital Miami, FL, USA).

Written informed consent was obtained from the legal guardian of the pediatric patient and from the patient that is an adult directly for publication of this case report.

Ana M. Duarte, MD is an investigator for Pfizer, Novartis, UCB Biopharma. She is also a speaker for Sanofi Regeneron, Pfizer, and Pierre Fabre. The other authors have no conflicts of interest relevant to this article to disclose.

No funding was obtained or utilized for this research.

Folasade F. Fayiga, MS:

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