The effects of isotretinoin therapy on the biliary system

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O R I G I N A L P A P E R

The effects of isotretinoin therapy on the biliary system

Gulcan Saylam Kurtipek

1

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Gözde Ulutas Demirbas

1

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Abdullah Demirbas

1

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Nihal Sar

ı

1

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Emre Zekey

1

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Fatma Tuncez Akyurek

1

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Gökhan Güngör

2

1

Department of Dermatology, Selcuk University Faculty of Medicine, Konya, Turkey

2

Department of Gastroenterology and Hepatology, Selcuk University Faculty of Medicine, Konya, Turkey

Correspondence

Gulcan Saylam Kurtipek, Selcuk University Faculty of Medicine, Department of Dermatology, Konya, Turkey. Email: gsaylamkurtipek@yahoo.com

Abstract

The aim of the present study was to investigate the potential effects of isotretinoin

on the biliary system in patients with acne vulgaris receiving isotretinoin therapy.

This was a preliminary retrospective study involving 40 patients with severe acne

vulgaris who attended the dermatology clinic and were administered different doses

(20 or 30 mg/day) of isotretinoin. Serum levels of AST, ALT, ALP, GGT, total bilirubin,

direct bilirubin, and indirect bilirubin at the beginning and at the first month of

ther-apy were scanned, recorded, and statistically analyzed. Total and indirect bilirubin

levels at the first month of treatment in 30 patients, receiving isotretinoin at a dose

of 20 mg/day, were significantly lower compared to the baseline values (p = .02 and

p = .03, respectively), whereas AST and GGT serum levels were significantly higher

(p = .003 and p = .006 respectively). No significant reduction in total and indirect

bili-rubin levels was detectable at the first month of treatment in 10 patients receiving

isotretinoin at a dose of 30 mg/day; however, AST, ALP, and GGT levels were

signifi-cantly elevated in these patients (p = .023; p = .004; and p = .001, respectively). To

our knowledge, there is no previous study investigating the effects of isotretinoin on

the biliary system, and, therefore, the present study is a preliminary one. Our findings

implicate that low dose (20 mg/day) isotretinoin therapy can potentially reduce total

and indirect bilirubin levels. Long-term, large-scale, prospective studies with patients

receiving different doses of isotretinoin may provide more reliable information

regarding the bilirubin lowering effects of isotretinoin and optimum dosing for

achieving this clinical effect.

K E Y W O R D S

acne, bilirubin, isotretinoin

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I N T R O D U C T I O N

Oral isotretinoin has dramatically influenced the field of dermatology after its approval by FDA in 1982 for the treatment of severe nodulocystic acne (Macek & Synthetic, 1982). Isotretinoin is a retinoic acid isomer that has been utilized for decades to treat resistant and severe acne. One of its most common adverse effects, encountered in ~2% of patients, is the elevation in serum transaminase levels (Vallerand et al., 2018).

Since oral retinoids are metabolized in the liver and mainly excreted by bile, it can be anticipated that patients with hepatic dys-function are more susceptible to hepatic side effects of these medica-tions (Brzezinski, Borowska, Chiriac, & Smigielski, 2017).

The aim of the present study was to investigate the potential effects of isotretinoin on the biliary system in patients with acne vulgaris receiving isotretinoin therapy. To our knowledge, the medical literature is devoid of any previous study investigating the effects of isotretinoin on the biliary system.

Received: 25 July 2019 Revised: 8 November 2019 Accepted: 23 November 2019 DOI: 10.1111/dth.13177

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P A T I E N T S A N D M E T H O D S

The study has a retrospective uncontrolled design. The medical files of patients were retrieved from medical archives according to which the patients who were admitted to our Dermatology Clinic and diag-nosed with severe acne vulgaris were prescribed different doses (20 or 30 mg/day) of isotretinoin between December 2017 and June 2018. Serum levels of aspartate aminotransferase (AST), alanine ami-notransferase (ALT), alkaline phosphatase (ALP), gamma-glutamyl transferase (GGT), total bilirubin, indirect bilirubin, direct bilirubin, were obtained before initiation of isotretinoin treatment (baseline), and at the first month of therapy they were retrospectively scanned, recorded, and analyzed statistically.

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R E S U L T S

Complete data belonging to 40 patients, with a mean age of 20.6 ± 3.37 years, was analyzed. The mean age of 29 female and 11 male patients were 20.4 ± 3.56 and 20,90 ± 2,94, respectively. There was no statistically significant difference between the mean ages of the two gen-ders (p = .703). Likewise, there was no statistically significant difference between the two genders in terms of baseline serum AST, ALT, total bili-rubin, direct bilirubin and indirect bilirubin values (p > .05).

The mean serum values of laboratory parameters at the beginning and at the first month of therapy in patients receiving isotretinoin 20 and 30 mg/day are given in Table 1.

In 30 patients receiving isotretinoin at a dose of 20 mg/day, total and indirect bilirubin levels at the first month of treatment were sig-nificantly lower compared to baseline values (p = .02 and p = .03, respectively). Although there was a trend for escalation in serum levels of other laboratory parameters (AST, ALT, ALP, and GGT), only

the rise in AST and GGT values attained statistical significance in this group (p = .003 and p = .006 respectively) (Table 1).

No significant reduction in total and indirect bilirubin levels was detectable at the first month of treatment in 10 patients receiving iso-tretinoin at a dose of 30 mg/day. However, there was a remarkable increase in serum AST, ALT, ALP, and GGT values and the elevations in serum AST, ALP, and GGT levels reached statistical significance (p = .023; p = .004; and p = .001, respectively) (Table 1).

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D I S C U S S I O N

Isotretinoin has long been used successfully in the treatment of severe acne. The medication has several adverse effects, notably hep-atotoxicity, elevation in serum lipids and mucocutaneous dryness (Brzezinski et al., 2017).

Monitoring of serum levels of hepatic enzymes and lipids before and during treatment is a routine procedure in evaluating patients who are prescribed isotretinoin therapy (Hansen et al., 2016; Kızılyel, Metin, Elmas, Çay_{ır, & Aktas¸, 2014; Vieira, Beijamini, & Melchiors, 2012).}

Several studies have focused on the hepatic side effects of iso-tretinoin (Webster, Webster, & Grimes, 2017). In their study of 110 patients undergoing isotretinoin therapy, Ataseven et al. have determined a statistically significant rise in serum AST values and a minimal increase in ALT values (Ataseven, Öztürk, & Dilek, 2013). In a retrospective cohort study by Zane et al. involving 13,772 patients, it was shown that 11% of patients had elevated transaminase levels (Zane, Leyden, Marqueling, & Manos, 2006). In our patients, statisti-cally significant elevation in serum AST, ALP, and GGT values was striking in patients receiving isotretinoin at a dose of 30 mg/day. Sig-nificant rise in AST and GGT serum levels was prominent even in the lower 20 mg/day dose group.

T A B L E 1 Mean serum values of laboratory parameters in patients receiving isotretinoin at a dose of 20 mg/ day and in those receiving 30 mg/day

20 mg/day p 30 mg/day p Total Bilirubina _{0,89 ± 0,67 mg/dl} _{0,82 ± 0,61 mg/dl} Total Bilirubinb _{0,75 ± 0,51 mg/dl} _.02c _{0,95 ± 0,71 mg/dl} _.24 _Indirect Bilirubina _{0,73 ± 0,57 mg/dl} _{0,66 ± 0,50 mg/dl} _Indirect Bilirubinb _{0,61 ± 0,44 mg/dl} _.03c _{0,79 ± 0,60 mg/dl} _.15 Direct Bilirubina _{0,16 ± 0,098 mg/dl} _{0,16 ± 0,11 mg/dl} Direct Bilirubinb _{0,15 ± 0,12 mg/dl} _.76 _{0,16 ± 0,11 mg/dl} _.87

ASTa _{19,0 ± 3,25 U/L} _{21,5 ± 9,05 U/L}

ASTb _{21,9 ± 6,21 U/L} _.003c _{25,5 ± 7,05 U/L} _.023c

ALTa _{14,06 ± 4,71 U/L} _{18,6 ± 6,34 U/L}

ALTb 16,1 ± 9,21 U/L .092 27,1 ± 20,77 U/L .116 ALPa 75,73 ± 33,4 U/L 73,6 ± 17,72 U/L

ALPb _{77,93 ± 33,64 U/L} _.10 _{80,1 ± 17,05 U/L} _.004c

GGTa _{15,86 ± 7,17 U/L} _{15,6 ± 5,25 U/L}

GGTb _{17,4 ± 6,81 U/L} _.006c _{19,9 ± 7,65 U/L} _.001c a

Pretreatment (baseline) serum values.

b_{Serum values at first month of therapy.} c_{Statistically significant (p < .05).}

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Isotretinoin is metabolized in the liver and excreted through the bile ducts. Potentially hepatotoxic medications such as isotretinoin, are incriminated to elevate both serum transaminase and bilirubin levels (Ahmad, 2015; Meloche & Besner, 1986). Thus, our observation of a bilirubin reduction effect by isotretinoin therapy is an unpredicted finding.

Paradoxically, there are reports of substantial reduction in serum bilirubin levels in patients with Gilbert syndrome, undergoing treat-ment with isotretinoin for concomitant acne (Le Gal & Pauwels, 1997). Gilbert syndrome is a hereditary disease characterized by mild unconjugated hyperbilirubinemia with an estimated prevalence of 6% (Aiso et al., 2017; Fernández-Crehuet, Fernández-Crehuet, Allam, & Fernández-Crehuet, 2014). We had the chance to observe remarkable reduction in bilirubin levels during the first month of isotretinoin ther-apy in one of our male patients with coexisting Gilbert syndrome and acne.

Many drugs such as phenobarbital and corticosteroids induce micro-somal enzymes such as uridine diphosphate glucuronosyltransferase (UDP-GT) and stimulate conjugation that culminates in reduction of bili-rubin levels (Rademaker, Wallace, Cunliffe, & Simpson, 1991).

The contradictory bilirubin-lowering effect of isotretinoin in patients with Gilbert syndrome may be explained based on two hypotheses: First, isotretinoin may potentially and reversibly reduce serum testosterone level, which in turn leads to an augmentation in UDP-GT activity. Alternatively, isotretinoin may increase the clear-ance of bilirubin by stimulating hepatocytes to produce more trans-forming carrier proteins or intracellular binding ligands that eliminate bilirubin, or it may increase the affinity of these enzymes for bilirubin (Wang, Jackson Jr, & Kaplan, 1995).

There is lack of information in the literature regarding the changes in bilirubin levels during isotretinoin therapy for acne. Based on our observation in one of our patients with Gilbert syndrome and acne, we planned a preliminary investigation of bilirubin levels in patients with acne treated with isotretinoin. Our study has several limitations. First, the number of patients enrolled is limited. Second, the patients lack laboratory data of further follow up visits; that is, lab-oratory parameters could only be evaluated at baseline and at the first month of treatment. Third, the number of patients receiving the higher 30 mg/day dose is one-third of those receiving the lower 20 mg/day dose.

Nevertheless, our findings implicate that low dose (20 mg/day) isotretinoin therapy has the potential to reduce total and indirect bilirubin levels, compared to baseline values. Our study fails to show a reduction in bilirubin levels at a higher dose (30 mg/day) of iso-tretinoin therapy. This finding may be attributed to a bias caused by a low number of patients in higher dose group, or it may simply imply that bilirubin-lowering effect of isotretinoin is lost at higher dosing.

Based on these encouraging results, we are planning a prospec-tive study of isotretinoin effects on the biliary system in patients with acne receiving differing doses of isotretinoin, with closer follow up of patients assessing laboratory parameters at monthly control visits. Long-term, large-scale, prospective studies enrolling patients receiving

different doses of isotretinoin may provide more reliable information regarding the bilirubin lowering effects of isotretinoin and optimum dosing for achieving this clinical effect. We believe that isotretinoin may represent a novel promising therapeutic option in diseases asso-ciated with hyperbilirubinemia and that in the future, new indications for isotretinoin therapy may arise in the field of gastroenterology and hepatology.

A C K N O W L E D G M E N T

This study was awarded the best research poster award at the_“27th National Dermatology Congress” held in Antalya, Turkey between 16 and 20 October 2018.

C O N F L I C T O F I N T E R E S T

The authors declare no conflict of interest.

O R C I D

Gulcan Saylam Kurtipek https://orcid.org/0000-0002-3106-4280

Fatma Tuncez Akyurek https://orcid.org/0000-0002-9339-8331

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Ataseven, A., Öztürk, P., & Dilek, N. (2013). Evaluation of laboratory parameters in patients receiving Isotretinoin for treatment of acne vulgaris. Turkish Journal of Dermatology, 7, 130–132.

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How to cite this article: Saylam Kurtipek G, Ulutas Demirbas G, Demirbas A, et al. The effects of isotretinoin therapy on the biliary system. Dermatologic Therapy. 2020;33: e13177.https://doi.org/10.1111/dth.13177