Acne is the most common skin disease among adolescents; it occurs in 80—90% of them. Taking into account that acne rashes are located mainly on open areas of the skin and can lead to the formation of persistent secondary changes (scars and hyper-pigmented spots), patients often develop psycho-emotional disorders — embarrassment, shame, depression, anxiety, hypochondriac syndrome [1, 2].

It’s well-known, the key factors in acne pathogenesis are an increase in sebum production, an imbalance of lipids secretion in the sebaceous glands, follicular hyperkeratosis, obstruction of the sebaceous glands ducts, colonization of the skin by Propionibacterium acnes bacteria and development of inflammatory changes in the area of sebaceous hair follicles. Recently, information has appeared that described events are preceded by development of subclinical inflammation in the area of sebaceous glands where triggers can be microorganisms, sebum lipids, neuropeptides released from nerve endings. Initiation of the inflammatory process involving toll-like receptors (TLR), protease-activated receptor—2 (PAR—2), and peroxisome proliferator-activated receptor (PPAR) is accompanied by migration and accumulation of leukocytes, the production of pro-inflammatory cytokines, antimicrobial peptides, impaired keratinization in the sebaceous glands, and the formation of micro-comedones [3—5].

The most effective treatment for severe acne is the systemic use of isotretinoin. The therapeutic effect of isotretinoin is realized not only through a powerful suppression of the sebocytes function, a decrease the size of the sebaceous glands, the normalization of keratinocyte keratinization but also due to a pronounced anti-inflammatory and immunomodulatory effect (a decrease in TLR2 expression on macrophages and the production of inflammatory mediators) [6, 7].

Isotretinoin is a drug with proven efficacy. The International Association of Dermatologists approves its use for the treatment of severe acne. To obtain a stable effect the drug is prescribed at a dose of 0.5—1 mg/kg/day for long courses (from 6 to 10 months) or until a cumulative dose of 120—150 mg/kg is reached [8].

When treated with isotretinoin approximately 2% of patients experience a number of side effects including an increase in the level of liver enzymes and triglycerides [9]. In most cases after discontinuation of therapy, the level of laboratory parameters returns to the baseline.

Special attention should be paid to questions on safety of this drug prescribing to patients with initially elevated bilirubin levels, for example, with Gilbert's syndrome.

Objective — assessment of the isotretinoin (Acnecutan) effect on the blood biochemical parameters (total and unconjugated bilirubin, ALT, AST and triglycerides) in patients suffering from severe acne and Gilbert's syndrome with an initially increased total bilirubin level.

Material and methods

A retrospective analysis of data from 20 patients with severe acne and treated with systemic isotretinoin (Acnecutan) was carried out. The study included patients of both genders aged 15 to 17 years inclusive (mean age 16 ± 0.63 years). The patients were divided into 2 age-matched groups. The main group consisted of 10 patients with Gilbert's syndrome confirmed in early childhood and an increased level of total bilirubin in the blood, the comparison group consisted of 10 patients without this pathology with normal blood biochemical parameters (total and unconjugated bilirubin, ALT, AST and triglycerides).

Patients of both groups received isotretinoin (Acnecutan) for acne at a standard dose of 0.5 mg /kg/day for 6 months. Before treatment, all patients signed a voluntary informed consent for therapy with this drug. The study assumed monthly visits to a dermatologist-venerologist to assess the clinical efficacy of therapy and titrate the dose of isotretinoin. The assessment of the skin process was carried out by counting the number of rash elements and determining the dermatological index of acne (DIA). Before treatment, as well as after 3 and 6 months the blood biochemical parameters (total and unconjugated bilirubin, ALT, AST and triglycerides) have been studied.

Results

The treatment trial of isotretinoin was 25 ± 1.24 weeks. During the treatment, the course dose of the drug was 100—120 mg/kg. As a treatment result with isotretinoin (Acnecutan) for 6 months, all patients included in the study achieved clinical remission (resolution of inflammatory elements — nodes, papules, pustules, open and closed comedones) (Fig. 1, 2). Some of the rashes have transformed into post-inflammatory spots, atrophic and hypertrophic scars. Dry skin was noted in 18 patients during therapy that was resolved by emollients applications (Perfectoin cream).

Fig. 1. Patient E., born in 2004.

a — before the start of therapy; b — after the end of therapy with isotretinoin Lidose in a daily dosage of 0.5 mg/kg, the course dose of the drug was equal to 112 mg/kg.

Fig. 2. Patient Z., born in 2006.

a — before the start of therapy; b — after the end of therapy with isotretinoin Lidose in a daily dosage of 0.5 mg/kg, the course dose of the drug was equal to 120 mg/kg.

The dynamics of blood biochemical parameters during the treatment is presented in the table. The baseline of total bilirubin before treatment in the main group was 39.22 ± 24.99 μmol/L that exceeded the same indicator (9.18 ± 2.58 μmol/L) in the control group by more than 2 times (p<0, 05). The same was observed for the level of unconjugated bilirubin — 9.78 ± 2.78 and 4.1 ± 0.61 μmol/l, respectively (p <0.05).

There were no differences in the content of ALT, AST and triglycerides before treatment between groups.

After 3 months of therapy, there was a tendency towards a decrease in the level of total bilirubin in all main group patients that persisted after 6 months of treatment. Other indicators both in the main and comparison groups did not change statistically significantly (Table).

Table. Dynamics of the biochemical parameters in patients’ blood serum during treatment with isotretinoin

6 months after the treatment in the main patients’ group with confirmed Gilbert's syndrome a paradoxical twofold decrease in the level of total bilirubin was noted (the differences from the baseline values are statistically significant). No significant changes in the content of unconjugated bilirubin and triglycerides were observed, although 7 ones showed a slight increase in the level of ALT, AST and triglycerides. Fluctuations in these indicators did not exceed the reference values and were not accompanied by appearance of complaints or any clinical symptoms during physical examination. Such fluctuations was regarded as clinically insignificant and did not require correction of daily dose or drug discontinuation.

In the comparison group, 6 months after the therapy in the absence of any changes in the total bilirubin level, ALT, AST and triglycerides, an increase in the average level of unconjugated bilirubin by 26.8% from the baseline was noted but no statistically significant differences were found. An increase in the level of unconjugated bilirubin was observed only in 4 (40%) patients while its average level remained within the reference values. Thus, fluctuations in the content of unconjugated bilirubin in the comparison group did not require a change in the dose of the drug or its discontinuation, as well as the prescription of additional drugs to correct the function of the hepatobiliary system.

Discussion

As retinoids are metabolized in the liver and mainly excreted in the bile it is logical to assume that the drug may adversely affect patients with hepatic dysfunction taking isotretinoin [10]. At the same time, there have been reports in the literature on a paradoxical decrease in serum bilirubin levels in patients with Gilbert's syndrome who received isotretinoin for acne [10, 11].

In one of the latest studies, a significant decrease in bilirubin level and less significant decrease in ALT and AST levels were found while taking a systemic retinoid [12]. However, despite the decrease in the average bilirubin level the value of this indicator remained above normal levels. In addition, after therapy discontinuation its amount returned to the baseline.

Several hypotheses have been proposed to explain this phenomenon. Thus, some studies have noted that bilirubin conjugation decrease during isotretinoin treatment is due to inhibition of microsomal enzymes such as aurikine diphosphate diphosphate glucanosyltransferase (UDP-GT). Other authors believe that main reason is a reversible decrease in serum testosterone levels that leads to an increase in UDP-GT activity. The hypothesis of the stimulating effect of isotretinoin on hepatocytes and the production of transport proteins that conjugate and remove bilirubin is also considered [13, 14].

Analysis of data showed that isotretinoin usage (Acnecutan) in patients suffering from Gilbert's syndrome led to a twofold decrease in the level of total bilirubin in the blood serum relative to the initial values. The dynamics of liver enzymes’ content (ALT, AST) and triglycerides did not differ from those in patients without this hereditary pathology. The use of isotretinoin (Acnecutan) in the comparison group did not lead to any clinically significant deviations in laboratory blood parameters.

In our study, the preference is given to isotretinoin produced by the Lidose technology (Acnecutan)^*. This drug allows reducing the amount of isotretinoin taken by 20% by increasing its bioavailability and thereby reducing the likelihood of developing adverse reactions that is a significant argument when choosing therapy in patients with Gilbert's syndrome and initially high blood levels of both total and conjugated bilirubin.

Conclusion

The described observations of isotretinoin Lidose on liver function allow concluding the relative safety of this drug in patients with acne and confirmed Gilbert's syndrome. Conducting prospective randomized blind studies among large groups will allow concluding how reliably isotretinoin reduces the level of bilirubin in patients receiving this drug including patients with Gilbert's syndrome. Revealing the exact mechanism of systemic retinoid effect on total bilirubin level also deserves attention of other specialties — gastroenterologists, hepatologists.

Authors’ contributions:

Attending physicians (selection of patients): D.A. Blinova, M.S. Kornyat, M.I. Proskurina, M.V. Urpin

Data and literature selection: D.A. Blinova, M.S. Kornyat, E.S. Negasheva, Z.V. Rassadina

The entire laboratory part: S.A. Polevshchikova

Statistical analysis: D.A. Blinova, E.S. Negasheva, I.V. Valitova

Drafting the manuscript: E.S. Negasheva, N.F. Zatorskaya, I.V. Valitova

The authors declare no conflicts of interest.

^*In Belgium, the drug is registered under the trade name Isosupra Lidose and is manufactured by Laboratories SMB S.A.