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The acne treatment isotretinoin (Roaccutane) increases the risk of blood changes linked to liver damage, reported two newspapers (August 22nd 2006). They accurately reported the results of a retrospective study, including the need for further research. One noted that the study did not concern isotretinoin cream prescribed in the UK.

On 22nd August 2006 two newspapers (1,2) reported that the side-effects of the acne treatment Isotretinoin, which is marketed in the UK as Roaccutane, may be more serious than was previously known. Both newspapers reported that the treatment was associated with increased levels of triglycerides, cholesterol and liver enzymes in the blood.
The newspaper reports were based on a retrospective study of 13, 772 patients in California who were prescribed oral isotretinoin for acne (3). The laboratory blood test results showed that, of those patients who had normal test results at baseline: 44% developed abnormal levels of triglycerides; 31% developed abnormal levels of cholesterol; and 11% developed abnormal levels of the liver enzyme transaminase during treatment. The study also found that after finishing treatment these results returned to normal or slightly raised levels in between 90 and 100% of patients tested.
Both newspapers accurately reported the conclusions of the study with one providing accurate details of the results (1). This report also correctly noted that in the UK isotretinoin is normally prescribed as a cream, and the study gives no indications that this would have similar effects to the oral preparation. Both newspapers reported the authors' view that further research is needed to establish whether patients who take isotretinoin have an increased risk of medical conditions associated with the changes in laboratory test results.

Evaluation of the evidence base for an increased risk of liver damage associated with isotretinoin.

Where does the evidence come from?

The evidence comes from research conducted by Dr Lee Zane and colleagues of the Departments of Dermatology and Epidemiology and Biostatistics at the University of California, San Francisco. The research was supported in part by the Dermatology Foundation.

What were the authors' objectives?

The objective was to assess the incidence of abnormal laboratory test results among isotretinoin users.

What was the nature of the evidence?

The study was an uncontrolled retrospective (cohort) study of 13,772 patients of the Kaiser Permanente Medical Care (KPNC) Program, Northern California who were treated for acne with oral isotretinoin between March 1995 and September 2002 and whose pharmacy records indicated that they had received at least one prescription for 4 weeks of treatment with isotretinoin. Patients were aged between 13 and 50, with half being less than 19. Where patients had undergone more than one course of isotretinoin therapy, only the first course was considered. Laboratory blood test data were used to assess whether patients' test results on a number of measures became abnormal during a treatment with isotretinoin. All data was obtained from the KPNC databases.

What were the factors of interest?

The outcomes of interest were the frequency of abnormal laboratory results, stratified by severity grade as defined by the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) for the following outcomes: serum triglycerides, total cholesterol, liver transaminase levels, white blood cell count, haemoglobin level, and platelet count. Results of tests at baseline (from 2 months before to 2 weeks after the start of treatment), and during and after treatment were compared.

What were the findings?

44% of patients who were within the normal range at baseline showed abnormally high levels of triglycerides during treatment, although moderate to severe abnormalities were only seen in 4% of patients. 31% of patients who were normal at baseline developed abnormally high levels of total cholesterol during treatment, with 0.1% being moderate or severe. 11% developed abnormal levels of the liver enzyme transaminase, with 1% being moderate or severe.

Of those patients who were tested after treatment had been discontinued 90% of those whose triglyceride level had become elevated returned to normal or mildly abnormal levels, as did 100% of those who had developed elevated total cholesterol, and 93% of those who had shown abnormal levels of transaminase.

What were the authors' conclusions?

The authors concluded that abnormally high serum lipid levels during treatment with isotretinoin may occur in a higher proportion of patients than was previously thought. The clinical significance of laboratory abnormalities during isotretinoin therapy remains to be determined.

How reliable are the conclusions?

This was a study of a large number of patients treated with isotretinoin. However, a cohort study cannot demonstrate a causal link between two events such as treatment with isotretinoin and abnormally high levels of triglycerides or liver enzymes in the blood, although it can demonstrate an association between them. In addition the study was undertaken retrospectively using medical records with blood test results not being available for all patients at all time points. In particular, the proportion of patients for whom data was available post-treatment was less than 20% for each outcome. This means that it is possible that, for example, patients with health problems were more likely to be tested than patients without such problems and that the test results consequently over-represent the proportion of all patients with abnormal levels of triglycerides, cholesterol and transaminase. It is also possible that patients who were taking other medications were more likely to undergo blood tests, and that abnormalities resulting from such medications were therefore over-represented in the patients tested.

The study cohort was clearly defined, but the authors note that it is not completely representative of the population from which it is drawn, with the highest and lowest economic strata being under-represented. In addition, the study was conducted in the USA, where isotretinoin is given as an oral preparation, whereas in the UK it is usually prescribed as a cream. This means that the results of the study cannot be generalised to apply to those treated with isotretinoin in the UK.

The findings of this study do not give any indication of whether treatment with isotretinoin increases the incidence of adverse events known to be associated with elevated results on the blood tests used, such as high blood pressure.

The validity of the authors' conclusions is to some extent limited by the issues outlined above. However, this was a large study, and its conclusions indicate the need for further, prospective research into the clinical significance of the widespread laboratory abnormalities found.

Systematic reviews

Information staff at CRD searched for systematic reviews relevant to this topic. Systematic reviews are valuable sources of evidence as they locate, appraise and synthesize all available evidence on a particular topic.

There were no related systematic reviews identified on the Cochrane Database of Systematic Reviews (CDSR) or on the Database of Abstracts of Reviews of Effects (DARE).