An adolescent with abdominal pain taking isotretinoin for severe acne.

Abstract: A 19-year-old female patient is presented who was taking isotretinoin for severe, nodulocystic acne. She subsequently developed abdominal pain during the course of treatment, thought to be related to an adverse reaction to the medication. A concerning side effect of isotretinoin is hypertriglyceridemia, which may be a cause of pancreatitis. A lipase level was determined to be elevated in this case. The patient was diagnosed with acute pancreatitis and the offending agent was discontinued. Clinicians need to be aware of the side effects when prescribing isotretinoin for recalcitrant acne.

Key Words: isotretinoin, hypertriglyceridemia, pancreatitis

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Isotretinoin is a retinoid derivative which is a highly effective drug in the treatment of severe, nodulocystic acne. Primarily prescribed by dermatologists for many years, this drug is now widely used in the primary care setting. Because of the emphasis placed on the teratogenic effects and the potential link to depression and increased suicidal ideation with use of isotretinoin, other side effects may go unnoticed. This case presents an adolescent female with a potential adverse reaction to isotretinoin. The literature regarding some of the untoward side effects related to use of isotretinoin is also reviewed.

Case Report

A 19-year-old female presented to the adolescent clinic complaining of recurrent abdominal pain for two weeks. She was taking isotretinoin for moderate to severe inflammatory acne. She described sharp, nonradiating, postprandial pain in the upper abdomen. There had been several episodes of emesis. The patient denied fever, headache, visual problems, chest pain, recent weight loss, constipation, diarrhea, or dysuria. She did admit to excessive dryness of the skin, especially around the lips, and a decreased appetite. Her psychological symptoms included increased agitation, mild anxiety and occasional feelings of sadness. However, she denied any suicidal ideations.

Past medical history was significant for major depression, dysfunctional uterine bleeding, and severe acne. Medications included sertraline 50 mg/d, ethinyl estradiol 35 [micro]g daily, and isotretinoin 60 mg/d, which had been started two months prior. She described absolute compliance with her current treatment regimen. Informed consent was obtained before initiating therapy for her acne. She had taken no pain medications, such as H2-blockers or nonsteroidal anti-inflammatories. There were no recent changes to her diet. She denied consumption of alcohol, use of tobacco products or illicit drugs, or sexual activity. The beginning of her last normal menstrual period was 2 days before presentation.

Initial laboratory values (before starting isotretinoin) included a negative pregnancy test, a nonfasting cholesterol of 182 mg/dL, with a triglyceride level of 151 mg/dL (<150 mg/dL). Liver function test revealed alkaline phosphatase 68 IU/L; SGOT 18 U/L; and SGPT 10 IU/L.

Vitals signs included a heart rate of 83 beats/min, blood pressure of 117/70, and an oral temperature of 98.0[degrees] Fahrenheit. Her weight was 110 pounds (BMI of 18.5). Physical examination revealed a well-developed, well-appearing female, in no apparent distress. Skin examination revealed significant facial pitting on the bilateral cheeks without new comedonal or inflammatory acne. Her chest and back were without lesions. Abdominal examination revealed some mild right epigastric tenderness without guarding or rebound and bowel sounds were active.

Follow-up labs included a pregnancy test which was negative, white blood cell count 4,800/mcL; hemoglobin 14 g/dL; and platelet count 225,000/dL; alkaline phosphatase 65 IU/L; SGOT 17 U/L; SGPT 11 IU/L; and a triglyceride level of 351 mg/dL. The serum amylase was 71 IU/L (0-88) and lipase was 95 U/L (16-63). The lipase level the following day increased to 109 U/L. This patient had acute pancreatitis secondary to use of isotretinoin, which was immediately discontinued.

Discussion

There have been multiple reports of side effects related to use of isotretinoin. As the use of this medication increases among medical providers in various disciplines, it is important to be aware of potential adverse reactions associated with isotretinoin. The more common complaints related to use of isotretinoin involve mucocutaneous changes. Due to the drying properties of the medication, patients may report irritation or burning of the skin, which occurs early on during treatment and improves over time. Dry eyes will occur in one third of patients taking isotretinoin. (1) Almost all patients will experience cheilitis. (1) The effect on the lips occurs immediately and has been reported in up to 93% of patients at the first visit. (2) As a result, proper anticipatory guidance and protection with a preferred lip balm is essential in ensuring compliance with the treatment. Lack of reporting of this symptom by the patient is an indication of inadequate use or noncompliance. (1)

Headaches may also occur with use of isotretinoin. A more serious concern is the association of isotretinoin with hypertension (IH). (3) A referral for an ophthalmologic evaluation for papilledema is warranted when unexplained headaches occur while on isotretinoin. When IH is suspected, it is recommended to cease therapy. A report has suggested resolution of symptoms within weeks to months; incidentally, a causal relationship between use of isotretinoin and IH was determined after reinitiation of treatment. (4) A similar side effect profile may occur with the tetracycline. Therefore, consideration should be taken not to prescribe both a retinoid and a tetracycline simultaneously for the treatment of recalcitrant acne.

The teratogenic effects related to use of isotretinoin during pregnancy has brought attention to the use of informed consent before treatment initiation. Isotretinoin has been associated with defects to multiple systems, to include central nervous system (CNS) and the cardiovascular system. (1) There is also an increased risk of spontaneous abortion. (1) Two negative pregnancy tests in females are imperative before isotretinoin is to be prescribed. Providers should encourage two forms of contraception in individuals who are sexually active. Concomitant use of oral contraceptives, started one month in advance, is required. Use of a combined oral contraceptive with low androgenic properties may be an added benefit for the treatment of acne. A pregnancy test should be performed at each subsequent clinic visit during the course of therapy, and oral contraceptive pills should be continued up to one month after treatment is completed.

There have been adverse reactions to isotretinoin reported to the Food and Drug Administration that have placed explicit warnings on the use of this drug, specifically, reports of depression and increased suicidal ideation. When severe acne may be the contributing factor in a teen with depression, isotretinoin, when prescribed with caution, may attenuate the depressive symptoms as the acne clears, improving self-esteem. (5) Consistent use of depressive scales can facilitate the identification of individuals on isotretinoin who may be exhibiting changes in their mood or increased suicidal thoughts. In these instances, it is recommended that the medication be discontinued and appropriate referrals for mental healthcare initiated. However, multiple reports indicate no link between use of isotretinoin and development of depression, although more research is indicated to identify those at increased risk for adverse outcomes. (5-8)

Hypertriglyceridemia has been linked with use of isotretinoin. Therefore, it is important to monitor levels at baseline and on a monthly basis, up to one month after cessation of isotretinoin. It has been suggested that individuals who have an increase in triglyceride levels after treatment may have a genetic predisposition to develop hyperlipidemia and the metabolic syndrome. (9-10) Liver enzymes should be routinely monitored due to concerns of drug-induced hepatitis.

In the presented patient, her triglyceride level at baseline was 152 mg/dL. After eight weeks on isotretinoin, her level increased to 351 mg/dL. In association with her abdominal pain and vomiting, the concern was that she might be developing pancreatitis. An elevated serum lipase level supported the diagnosis. There have been several reports indicating a drug-induced pancreatitis related to hypertyriglyceridemia. (11-13) Each of these cases reported a serum triglyceride level greater than 800 mg/dL. Caution should be taken when levels reach higher than 500 mg/dL. This patient had a mild elevation of her triglycerides with evidence of inflammation of the pancreas, as cases can range from mild to severe. Other common drugs prescribed to teenagers that may be associated with drug-induced pancreatitis include estrogens, valproic acid, nonsteroidal anti-inflammatories, metronidazole, and tetracycline. (11) This patient was taking ethinyl estradiol 35 [micro]g, a potential cause of pancreatitis, which was continued due to the teratogenic concerns of isotretinoin. Pancreatitis, more commonly caused by alcohol abuse, is linked to an offending drug in 2% of cases. (11) Attention should be given to patients taking isotretinoin who present with acute abdominal pain. Providers may want to consider ordering serum amylase and lipase levels during the treatment course of patients taking isotretinoin.

Conclusion

Isotretinoin is a very effective drug for treatment of acne in patients who have otherwise failed treatment with traditional medications, such as systemic antibiotics. Despite this efficacy, isotretinoin has significant side effects which warrant monitoring. Following the prescribing guidelines for isotretinoin will aid in the prevention and amelioration of these adverse reactions, and, at the same time, increase the quality of life of the developing adolescent.

References

1. Ellis CN, Krach KJ. Uses and complications of isotretinoin therapy. J Am Acad Dermatol 2001;45:S150-S157.

2. Hull PR. Demkiw-Bartel C. Isotretinoin use in acne: prospective evaluation of adverse events. J Cutan Med Surg 2000;4:66-70.

3. Fraunfelder FW, Fraunfelder FT, Corbett JJ. Isotretinoin-associated intracranial hypertension. Ophthalmology 2004;111:1248-1250.

4. Fraunfelder FW, Fraunfelder FT. Evidence for a probable causal relationship between tretinoin, acitretin, and etretinate and intracranial hypertension. J Neuroophthalmol 2004;24:214-216.

5. Chia CY, Lane W, Chibnall J, et al. Isotretinoin therapy and mood changes in adolescents with moderate to severe acne: a cohort study. Arch Dermatol 2005;141:557-60.

6. Jick SS, Kremers HM, Vasilakis-Scaramozza C. Isotretinoin use and risk of depression, psychotic symptoms, suicide, and attempted suicide. Arch Dermatol 2000;136:1231-1236.

7. Jacobs DG, Deutsch NL, Brewer M. Suicide, depression, and isotretinoin: is there a causal link? J Am Acad Dermatol 2001:45:S168-S175.

8. Wysowski DK, Pitts M, Beitz J. An analysis of reports of depression and suicide in patients treated with isotretinoin. J Am Acad Dermatol 2001;45:515-519.

9. Rodondi N, Darioli R, Ramelet AA, et al. High risk for hyperlipidemia and the metabolic syndrome after an episode of hypertriglyceridemia during 13-cis retinoic acid therapy for acne: a pharmacogenetic study. Ann Intern Med 2002; 136:582-589.

10. Cortese C, Corona R. Taking advantage of a side effect of isotretinoin. Arch Dermatol 2003;139:376-377.

11. Jamshidi M, Obermeyer RJ, Govindaraj S, et al. Acute pancreatitis secondary to isotretinoin-induced hyperlipidemia. J Okla State Med Assoc 2002;95:79-80.

12. McCarter TL, Chen YK. Marked hyperlipidemia and pancreatitis associated with isotretinoin therapy. Am J Gastroenterol 1992;87:1855-1858.

13. Flynn WJ, Freeman PG, Wickboldt LG. Pancreatitis associated with isotretinoin-induced hypertriglyceridemia. Ann Intern Med 1987;107:63.

It's stasis that kills you off in the end, not ambition.
--Bono

Jeffery P. Greene, MD

From the Department of Pediatrics, Fort Sam Houston, Houston, TX.

Reprint requests to Jeffery P. Greene, MD, Department of Pediatrics, 3851 Roger Brooke Drive, Fort Sam Houston, Houston, TX 78234. Email: [e-mail]

The views expressed in this article are those of the author's and do not reflect the official policy of the Army Medical Department, Department of the Army, the Department of Defense, or the U.S. Government.

Accepted April 7, 2006,

RELATED ARTICLE: Key Points

* Use of isotretinoin in teenagers for recalcitrant acne treatment is becoming more common.

* Abdominal pain with concomitant use of isotretinoin may be indicative of pancreatic disease rather than liver pathology.

* In addition to common side effects of isotretinoin, attention to the possibility of drug-induced pancreatitis related to hypertriglyceridemia should be made.