Figure 1.  CONSORT Diagram

ANOVA indicates analysis of variance.

aExcluded full-text articles are listed in eTable 3 in the Supplement.

Figure 2.  Measures for Triglycerides

Separate analyses were performed for triglyceride values at various points in time, including mean (99% CI) nonbaseline values (A) and mean differences from baseline to mean follow-up (B). The National Institutes of Health Clinical Center reference value for high risk for triglycerides is 200 mg/dL. For the graph showing the mean difference from baseline to mean follow-up (B), a negative value indicates a decreased value at follow-up; a positive value, an increased value. SI conversion factor: To convert to millimoles per liter, multiply by 0.0113.

Figure 3.  Measures for Total Cholesterol (TC)

Separate analyses were performed for TC values at various points in time, including mean (99% CI) nonbaseline values (A) and mean differences from baseline to mean follow-up (B). The National Institutes of Health Clinical Center reference value for high risk for TC level is 240 mg/dL. For the graph showing the mean difference from baseline to mean follow-up (B), a negative value indicates a decreased value at follow-up; a positive value, an increased value. SI conversion factor: To convert to millimoles per liter, multiply by 0.0259.

Figure 4.  Measures for Aspartate Aminotransferase (AST)

Separate analyses were performed for AST values at various points in time, including mean (99% CI) nonbaseline values (A) and mean differences from baseline to mean follow-up (B). The Common Terminology Criteria for Adverse Events reference value for grade 2 abnormality for AST is 108 U/L. For the graph showing the mean difference from baseline to mean follow-up (B), a negative value indicates a decreased value at follow-up; a positive value, an increased value. SI conversion factor: To convert to microkatals per liter, multiply by 0.0167.

Figure 5.  Measures for Alanine Aminotransferase (ALT)

Separate analyses were performed for ALT and AP values at various points in time, including mean (99% CI) nonbaseline ALT values (A) and mean differences from ALT baseline to follow-up (B). The Common Terminology Criteria for Adverse Events reference values for grade 2 abnormality for ALT is 111 U/L and for AP is 367.5 U/L, and the Merck Manual reference ranges for ALT and AP are 0 to 35 U/L and 36 to 92 U/L, respectively. For the graph showing the mean difference from baseline to mean follow-up (B), a negative value indicates a decreased value at follow-up; a positive value, an increased value. SI conversion factor: To convert to microkatals per liter, multiply by 0.0167.

1.
Vieira  AS, Beijamini  V, Melchiors  AC.  The effect of isotretinoin on triglycerides and liver aminotransferases.  An Bras Dermatol. 2012;87(3):382-387.PubMedGoogle ScholarCrossref
2.
Flynn  WJ, Freeman  PG, Wickboldt  LG.  Pancreatitis associated with isotretinoin-induced hypertriglyceridemia.  Ann Intern Med. 1987;107(1):63.PubMedGoogle ScholarCrossref
3.
Zane  LT, Leyden  WA, Marqueling  AL, Manos  MM.  A population-based analysis of laboratory abnormalities during isotretinoin therapy for acne vulgaris.  Arch Dermatol. 2006;142(8):1016-1022.PubMedGoogle ScholarCrossref
4.
Roche Laboratories. Accutane (isotretinoin capsules). http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/018662s059lbl.pdf. Published November 2008. Accessed July 5, 2014.
5.
Alcalay  J, Landau  M, Zucker  A.  Analysis of laboratory data in acne patients treated with isotretinoin: is there really a need to perform routine laboratory tests?  J Dermatolog Treat. 2001;12(1):9-12.PubMedGoogle ScholarCrossref
6.
Barth  JH, Macdonald-Hull  SP, Mark  J, Jones  RG, Cunliffe  WJ.  Isotretinoin therapy for acne vulgaris: a re-evaluation of the need for measurements of plasma lipids and liver function tests.  Br J Dermatol. 1993;129(6):704-707.PubMedGoogle ScholarCrossref
7.
Altman  RS, Altman  LJ, Altman  JS.  A proposed set of new guidelines for routine blood tests during isotretinoin therapy for acne vulgaris.  Dermatology. 2002;204(3):232-235.PubMedGoogle ScholarCrossref
8.
Hansen  T, Zaenglein  A, Miller  J.  Standardizing laboratory monitoring of patients undergoing isotretinoin treatment using a cost-effective and best evidence approach [abstract].  J Am Acad Dermatol. 2013;68(4)(suppl 1):AB6.Google Scholar
9.
University of York Centres for Reviews and Dissemination.  PROSPERO database: laboratory monitoring during treatment with isotretinoin. Registration CRD42014010494. http://www.crd.york.ac.uk/prospero. Accessed July 3, 2014.
10.
National Institutes of Health.  Clinical Center Test Guide: Lipid Panel. Washington, DC: US Dept of Health and Human Services; 2015.
11.
National Institutes of Health.  Clinical Center Test Guide: Hepatic Panel. Washington, DC: US Dept of Health and Human Services; 2015.
12.
Ragos  G, Houlden  R, Danby  FW.  Effect of isotretinoin therapy on serum total cholesterol and triglycerides.  Can J Clin Pharmacol. 1998;5(1):43-47.Google Scholar
13.
Buckley  D, Rogers  S, Daly  P.  Isotretinoin therapy for acne vulgaris: results in an Irish population.  Ir J Med Sci. 1990;159(1):2-5.PubMedGoogle ScholarCrossref
14.
Erturan  İ, Naziroğlu  M, Akkaya  VB.  Isotretinoin treatment induces oxidative toxicity in blood of patients with acne vulgaris: a clinical pilot study.  Cell Biochem Funct. 2012;30(7):552-557.PubMedGoogle ScholarCrossref
15.
Michaëlsson  G, Vahlquist  A, Mobacken  H,  et al.  Changes in laboratory variables induced by isotretinoin treatment of acne.  Acta Derm Venereol. 1986;66(2):144-148.PubMedGoogle Scholar
16.
Bershad  S, Rubinstein  A, Paterniti  JR,  et al.  Changes in plasma lipids and lipoproteins during isotretinoin therapy for acne.  N Engl J Med. 1985;313(16):981-985.PubMedGoogle ScholarCrossref
17.
Hanstad  IK, Thune  P.  Nodulocystic acne: treatment with isotretinoin (Roaccutan)—quantitative measures of skin lipids [in Norwegian].  Tidsskr Nor Laegeforen. 1985;105(23):1497-1500.PubMedGoogle Scholar
18.
Pigatto  PD, Finzi  AF, Altomare  GF, Polenghi  MM, Vergani  C, Vigotti  G.  Isotretinoin versus minocycline in cystic acne: a study of lipid metabolism.  Dermatologica. 1986;172(3):154-159.PubMedGoogle ScholarCrossref
19.
Laker  MF, Green  C, Bhuiyan  AK, Shuster  S.  Isotretinoin and serum lipids: studies on fatty acid, apolipoprotein and intermediary metabolism.  Br J Dermatol. 1987;117(2):203-206.PubMedGoogle ScholarCrossref
20.
Melnik  B, Bros  U, Plewig  G.  Characterization of apoprotein metabolism and atherogenic lipoproteins during oral isotretinoin treatment.  Dermatologica. 1987;175(suppl 1):158-168.PubMedGoogle ScholarCrossref
21.
Lyons  F, Laker  MF, Marsden  JR, Manuel  R, Shuster  S.  Effect of oral 13-cis-retinoic acid on serum lipids.  Br J Dermatol. 1982;107(5):591-595.PubMedGoogle ScholarCrossref
22.
Jones  DH, King  K, Miller  AJ, Cunliffe  WJ.  A dose-response study of I3-cis-retinoic acid in acne vulgaris.  Br J Dermatol. 1983;108(3):333-343.PubMedGoogle ScholarCrossref
23.
Strauss  JS, Rapini  RP, Shalita  AR,  et al.  Isotretinoin therapy for acne: results of a multicenter dose-response study.  J Am Acad Dermatol. 1984;10(3):490-496.PubMedGoogle ScholarCrossref
24.
Ostlere  LS, Harris  D, Morse-Fisher  N, Wright  S.  Effect of systemic administration of isotretinoin on blood lipids and fatty acids in acne patients.  Int J Dermatol. 1996;35(3):216-218.PubMedGoogle ScholarCrossref
25.
Strauss  JS, Leyden  JJ, Lucky  AW,  et al.  Safety of a new micronized formulation of isotretinoin in patients with severe recalcitrant nodular acne: a randomized trial comparing micronized isotretinoin with standard isotretinoin.  J Am Acad Dermatol. 2001;45(2):196-207.PubMedGoogle ScholarCrossref
26.
Ferahbas  A, Turan  MT, Esel  E, Utas  S, Kutlugun  C, Kilic  CG.  A pilot study evaluating anxiety and depressive scores in acne patients treated with isotretinoin.  J Dermatolog Treat. 2004;15(3):153-157.PubMedGoogle ScholarCrossref
27.
Koistinen  HA, Remitz  A, Koivisto  VA, Ebeling  P.  Paradoxical rise in serum adiponectin concentration in the face of acid-induced insulin resistance 13-cis-retinoic.  Diabetologia. 2006;49(2):383-386.PubMedGoogle ScholarCrossref
28.
Polat  M, Lenk  N, Bingöl  S,  et al.  Plasma homocysteine level is elevated in patients on isotretinoin therapy for cystic acne: a prospective controlled study.  J Dermatolog Treat. 2008;19(4):229-232.PubMedGoogle ScholarCrossref
29.
Roodsari  MR, Akbari  MR, Sarrafi-rad  N, Saeedi  M, Gheisari  M, Kavand  S.  The effect of isotretinoin treatment on plasma homocysteine levels in acne vulgaris.  Clin Exp Dermatol. 2010;35(6):624-626.PubMedGoogle ScholarCrossref
30.
Ertugrul  DT, Karadag  AS, Tutal  E, Akin  KO.  Isotretinoin does not induce insulin resistance in patients with acne.  Clin Exp Dermatol. 2011;36(2):124-128.PubMedGoogle ScholarCrossref
31.
Dursun  R, Alpaslan  M, Caliskan  M,  et al.  Isotretinoin does not prolong QT intervals and QT dispersion in patients with severe acne: a surprising finding for a drug with numerous side effects.  J Drugs Dermatol. 2011;10(7):710-714.PubMedGoogle Scholar
32.
Karadag  AS, Tutal  E, Ertugrul  DT, Akin  KO.  Effect of isotretinoin treatment on plasma holotranscobalamin, vitamin B12, folic acid, and homocysteine levels: non-controlled study.  Int J Dermatol. 2011;50(12):1564-1569.PubMedGoogle ScholarCrossref
33.
Koistinen  HA, Remitz  A, Gylling  H, Miettinen  TA, Koivisto  VA, Ebeling  P.  Dyslipidemia and a reversible decrease in insulin sensitivity induced by therapy with 13-cis-retinoic acid.  Diabetes Metab Res Rev. 2001;17(5):391-395.PubMedGoogle ScholarCrossref
34.
Rødland  O, Aksnes  L, Nilsen  A, Morken  T.  Serum levels of vitamin D metabolites in isotretinoin-treated acne patients.  Acta Derm Venereol. 1992;72(3):217-219.PubMedGoogle Scholar
35.
Hoting  VE, Schütte  B, Schirren  C.  Isotretinoin treatment of acne conglobate: andrologic follow-up [in German].  Fortschr Med. 1992;110(23):427-430.PubMedGoogle Scholar
36.
Bruhat  MA, Mage  G, Manhes  H, Pouly  JL, Jacquetin  B.  The indication for laparoscopy in female infertility [in French].  J Gynecol Obstet Biol Reprod (Paris). 1980;9(3):337-340.PubMedGoogle Scholar
37.
Meigel  W, Gollnick  H, Wokalek  H, Plewig  G.  Oral treatment of acne conglobata using 13-cis-retinoic acid: results of the German multicentric study following 24 weeks of treatment [in German].  Hautarzt. 1983;34(8):387-397.PubMedGoogle Scholar
38.
Plewig  G, Gollnick  H, Meigel  W, Wokalek  H.  13-Cis retinoic acid in the oral therapy of acne conglobate: results of a multi-center study [in German].  Hautarzt. 1981;32(12):634-646.PubMedGoogle Scholar
39.
Wagner  A, Plewig  G.  13-Cis-retinoic acid: pharmacologic and toxicologic findings in treatment of severe forms of acne [in German].  MMW Munch Med Wochenschr. 1980;122(38):1294-1300.PubMedGoogle Scholar
40.
Effects of isotretinoin on plasma lipids and lipoproteins.  Nutr Rev. 1986;44(6):196-198.PubMedGoogle Scholar
41.
Zech  LA, Gross  EG, Peck  GL, Brewer  HB.  Changes in plasma cholesterol and triglyceride levels after treatment with oral isotretinoin: a prospective study.  Arch Dermatol. 1983;119(12):987-993.PubMedGoogle ScholarCrossref
42.
Ertam  I, Alper  S, Unal  I.  Is it necessary to have routine blood tests in patients treated with isotretinoin?  J Dermatolog Treat. 2006;17(4):214-216.PubMedGoogle ScholarCrossref
43.
Wahab  R, Rahman  M, Monamie  N, Jamaluddin  M, Khondker  L, Afroz  W.  Isotretinoin vs weekly pulse dose azithromycin in the treatment of acne—a comparative study.  J Pak Assoc Dermatol. 2008;18:9-14.Google Scholar
44.
Agarwal  US, Besarwal  RK, Bhola  K.  Oral isotretinoin in different dose regimens for acne vulgaris: a randomized comparative trial.  Indian J Dermatol Venereol Leprol. 2011;77(6):688-694.PubMedGoogle ScholarCrossref
45.
Ahmed  I, Wahid  Z, Nasreen  S.  Adverse effects of systemic isotretinoin therapy: a study of 78 patients.  J Pak Assoc Dermatol. 2005;15:242-246.Google Scholar
46.
Tallab  T, Joharji  H, Jazei  M, Bahamdan  K, Ibrahim  K, Karkashan  E.  Isotretinoin therapy: any need for laboratory assessment?  West Afr J Med. 2004;23(4):273-275.PubMedGoogle Scholar
47.
Sadick  NA.  Practitioner’s 10-year experience with isotretinoin and side effect profiles.  Int J Cosmet Surg Aesthetic Dermatol. 2002;4(2):89-94.Google ScholarCrossref
48.
Ng  PP, Goh  CL.  Treatment outcome of acne vulgaris with oral isotretinoin in 89 patients.  Int J Dermatol. 1999;38(3):213-216.PubMedGoogle ScholarCrossref
49.
Spear  KL, Muller  SA.  Treatment of cystic acne with 13-cis-retinoic acid.  Mayo Clin Proc. 1983;58(8):509-514.PubMedGoogle Scholar
50.
Hermes  B, Praetel  C, Henz  BM.  Medium dose isotretinoin for the treatment of acne.  J Eur Acad Dermatol Venereol. 1998;11(2):117-121.PubMedGoogle ScholarCrossref
51.
van der Meeren  HL, van der Schroeff  JG, Stijnen  T, van Duren  JA, van der Dries  HA, van Voorst Vader  PC.  Dose-response relationship in isotretinoin therapy for conglobate acne.  Dermatologica. 1983;167(6):299-303.PubMedGoogle ScholarCrossref
52.
Shahidullah  M, Tham  SN, Goh  CL.  Isotretinoin therapy in acne vulgaris: a 10-year retrospective study in Singapore.  Int J Dermatol. 1994;33(1):60-63.PubMedGoogle ScholarCrossref
53.
Kaymak  Y, Ilter  N.  The results and side effects of systemic isotretinoin treatment in 100 patients with acne vulgaris.  Dermatol Nurs. 2006;18(6):576-580.PubMedGoogle Scholar
54.
Cyrulnik  AA, Viola  KV, Gewirtzman  AJ, Cohen  SR.  High-dose isotretinoin in acne vulgaris: improved treatment outcomes and quality of life.  Int J Dermatol. 2012;51(9):1123-1130.PubMedGoogle ScholarCrossref
55.
Gandola  M.  Therapy of severe acne and acne rosacea with oral 13-cis-retinoic acid (isotretinoin) [in Italian].  Acta Vitaminol Enzymol. 1984;6(4):325-337.PubMedGoogle Scholar
56.
Bruno  NP, Beacham  BE, Burnett  JW.  Adverse effects of isotretinoin therapy.  Cutis. 1984;33(5):484-486, 489.PubMedGoogle Scholar
57.
Entezari-Maleki  T, Hadjibabaeil  M, Salamzadeh  J, Javadil  MR, Shalviri  G, Gholamil  K.  Evaluation and monitoring of isotretinoin use in Iran.  Arch Iran Med. 2012;15(7):409-412.Google Scholar
58.
Gollnick  H, Luley  C, Schwartzkopff  W, Orfanos  CE.  Changes in serum lipid fractions as a side effect of oral retinoids [in German].  Z Hautkr. 1982;57(17):1255-1267.PubMedGoogle Scholar
59.
O’Leary  TJ, Simo  IE, Kanigsberg  N, Walker  J, Goodall  JC, Ooi  TC.  Changes in serum lipoproteins and high-density lipoprotein composition during isotretinoin therapy.  Clin Invest Med. 1987;10(4):355-360.PubMedGoogle Scholar
60.
Amblard  P, Beani  JC, Reymond  JL, Didier  B, Coignet  M.  Our experience of isotretinoin in the treatment of severe acne for about 421 treated patients [in French].  Sem Hop Ther Paris. 1986;62(1-2):61-66.Google Scholar
61.
Almond-Roesler  B, Blume-Peytavi  U, Bisson  S, Krahn  M, Rohloff  E, Orfanos  CE.  Monitoring of isotretinoin therapy by measuring the plasma levels of isotretinoin and 4-oxo-isotretinoin: a useful tool for management of severe acne.  Dermatology. 1998;196(1):176-181.PubMedGoogle ScholarCrossref
62.
McElwee  NE, Schumacher  MC, Johnson  SC,  et al.  An observational study of isotretinoin recipients treated for acne in a health maintenance organization.  Arch Dermatol. 1991;127(3):341-346.PubMedGoogle ScholarCrossref
63.
Al-Mutairi  N, Manchanda  Y, Nour-Eldin  O, Sultan  A.  Isotretinoin in acne vulgaris: a prospective analysis of 160 cases from Kuwait.  J Drugs Dermatol. 2005;4(3):369-373.PubMedGoogle Scholar
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### Citation

Lee YH, Scharnitz TP, Muscat J, Chen A, Gupta-Elera G, Kirby JS. Laboratory Monitoring During Isotretinoin Therapy for Acne: A Systematic Review and Meta-analysis. JAMA Dermatol. 2016;152(1):35–44. doi:10.1001/jamadermatol.2015.3091

Original Investigation
January 2016

# Laboratory Monitoring During Isotretinoin Therapy for Acne: A Systematic Review and Meta-analysis

Author Affiliations
• 1Division of Dermatology, Sharp Rees-Stealy Medical Group, San Diego, California
• 2Penn State College of Medicine, Hershey, Pennsylvania
• 3Department of Public Health Sciences, Penn State Milton S. Hershey Medical Center, Hershey, Pennsylvania
• 4Department of Dermatology, Penn State Milton S. Hershey Medical Center, Hershey, Pennsylvania
JAMA Dermatol. 2016;152(1):35-44. doi:10.1001/jamadermatol.2015.3091
Abstract

Importance  Oral isotretinoin has been associated with several adverse effects, but evidence-based estimates of laboratory changes during isotretinoin therapy in large patient samples are limited.

Objective  To develop estimates of the laboratory changes that occur during isotretinoin therapy for acne using extant data and meta-analytic methods.

Data Sources  A comprehensive search strategy using Ovid/MEDLINE, EMBASE, and gray literature was conducted (1960-August 1, 2013) to identify all relevant studies of isotretinoin use in acne vulgaris. Terms related to acne treatment, isotretinoin, and diagnostic procedures were searched with all available synonyms.

Study Selection  Inclusion criteria consisted of clinical trials using oral isotretinoin, doses of 40 mg/d or more, duration of at least 4 weeks, patients aged 9 to 35 years with acne vulgaris, and 10 or more participants. Studies from all countries published in any language were included. Exclusion criteria were use of modified isotretinoin products, isotretinoin therapy for conditions other than acne vulgaris, and concomitant acne therapy. The initial search yielded 342 records; 116 of these were screened for full-text examination.

Data Extraction and Synthesis  Two authors independently reviewed the publications to determine eligibility, and disagreements were resolved by a third author. Generated weighted means and 99% CIs were calculated using the reported means (SDs or SEs). A random effects model was created, and statistical heterogeneity was quantified. Data were analyzed from August 25, 2014, to December 4, 2015.

Main Outcomes and Measures  Laboratory values for lipid levels, hepatic function, and complete blood cell count were evaluated.

Results  Data from 61 of the 116 studies were evaluated; 26 studies (1574 patients) were included in the meta-analysis. The mean (99% CI) values during treatment (nonbaseline) for triglycerides was 119.98 mg/dL (98.58-141.39 mg/dL); for total cholesterol, 184.74 mg/dL (178.17-191.31 mg/dL); for low-density lipoprotein cholesterol, 109.23 mg/dL (103.68-114.79 mg/dL); for high-density lipoprotein cholesterol, 42.80 mg/dL (39.84-45.76 mg/dL); for aspartate aminotransferase, 22.67 U/L (19.94-25.41 U/L); for alanine aminotransferase, 21.77 U/L (18.96-24.59 U/L); for alkaline phosphatase, 88.35 U/L (58.94-117.76 U/L); and for white blood cell count, 6890/µL (5700/µL-8030/µL). This meta-analysis showed that (1) isotretinoin is associated with a statistically significant change in the mean value of several laboratory tests (white blood cell count and hepatic and lipid panels), yet (2) the mean changes across a patient group did not meet a priori criteria for high-risk and (3) the proportion of patients with laboratory abnormalities was low.

Conclusions and Relevance  The evidence from this study does not support monthly laboratory testing for use of standard doses of oral isotretinoin for the standard patient with acne.

Introduction

Severe nodulocystic acne can be treated with isotretinoin, which can result in dramatic improvement within months. Although very effective, isotretinoin has been associated1-3 with several adverse effects, including teratogenicity, hyperlipidemia and associated pancreatitis, leukopenia, thrombocytopenia, and transaminitis. Monitoring of pregnancy during therapy is mandated via the iPLEDGE program (https://www.ipledgeprogram.com). The package insert4 recommends baseline fasting lipid and hepatic panels with repeated testing at weekly or biweekly intervals until “the response has been established.” There are no specific suggestions in the document for laboratory monitoring.

Prior studies have investigated the usefulness of laboratory monitoring during isotretinoin therapy and made recommendations ranging from performance of only baseline testing5 to baseline testing with 1 follow-up set of tests.6,7 The latter recommendations were based on samples of approximately 140 to 200 patients and at single centers.6,7 In addition, Hansen et al8 reviewed 574 isotretinoin courses for 515 patients and found that grade 2 abnormalities were uncommon (0.2%-1.6% of patients) and 67.7% of the abnormalities occurred within the first 60 days of treatment. Nevertheless, overall, the evidence to guide laboratory monitoring during isotretinoin therapy is limited by differences in tests ordered, testing frequency, and small sample sizes in some studies. The aim of this systematic review and meta-analysis was to combine data across multiple published studies to develop estimates of laboratory changes during isotretinoin therapy for acne.

Methods

A systematic review and meta-analysis were performed. The study was registered with the PROSPERO International prospective register of systematic reviews.9 The PRISMA and AMSTAR checklists were used to guide the project (eAppendix 1 in the Supplement).

Search Strategy

We conducted a comprehensive search strategy designed by a Master of Library and Information Science–trained librarian to identify all relevant studies of oral isotretinoin use in adolescents and adults (age 9-35 years) with acne vulgaris. Articles in any language were included; all searches covered 1960 to August 1, 2013. A comprehensive search was performed in MEDLINE using the Ovid platform. The search terms related to acne treatment, isotretinoin, and diagnostic procedures were searched with all available synonyms. A second search of EMBASE was performed through Proquest. Duplicate citations were removed. A final search for relevant gray literature was performed on Google Scholar with citations and patents removed. A complete description of the search methods is described in eAppendix 2 of the Supplement.

Selection Criteria

Inclusion criteria were developed a priori and included studies of acne vulgaris, use of oral isotretinoin (altered sustained-release or lipid-enhanced products were excluded), dose regimens of 40 mg or more daily (or ≥0.5 mg/kg), duration of treatment for at least 4 weeks, and treatment of children and adults (aged 9-35 years). Studies with a cohort or comparison design as well as case series of 10 or more participants were eligible. The study must have reported values for the laboratory tests of interest: complete blood cell count, hepatic panel (aspartate aminotransferase [AST], alanine aminotransferase [ALT], and alkaline phosphatase [AP]), and/or lipid panel (triglycerides [TG], total cholesterol, low-density lipoprotein cholesterol [LDL-C], and high-density lipoprotein cholesterol [HDL-C]). Studies were separated into 2 groups; those that reported mean values for laboratory tests were included in the meta-analysis, and studies that reported the proportion of patients with an abnormal test were described separately in a narrative review.

Study Selection

Titles and abstracts from the search results were screened, and full articles of all citations that met the predefined selection criteria were obtained for review. Subsequently, full articles were examined for inclusion or exclusion and data extraction. Two reviewers (T.P.S. and G.G.-E.) independently assessed each potentially relevant study for eligibility. Disagreements were resolved by a third reviewer (Y.H.L.).

Data Extraction

The selected studies were reviewed and the data were abstracted by one of us (T.P.S.); the accuracy was confirmed by another one of us (Y.H.L.). Information was entered into a Google document (Google Inc) and included study characteristics (country, design, sample size, and duration of therapy), patient characteristics (age and sex), and therapeutic interventions (isotretinoin dose and treatment duration). Laboratory tests of interest included the complete blood cell count, hepatic panel (AST, ALT, and AP), and lipid panel (TG, total cholesterol, HDL-C, and LDL-C). The timing of laboratory monitoring during isotretinoin therapy (eg, at week 6, month 1, and month 3) was recorded. The mean (SD) of the laboratory result and the proportion of patients with abnormal results were recorded. Studies that did not report specific values at identified time points were not included in the meta-analysis, but their findings are described in a separate narrative. The National Institutes of Health Clinical Center reference ranges10 were used to define significant or high-risk laboratory changes for white blood cell count, which corresponded to 3000 cells/µL (to convert to × 109/L, multiply by 0.001), TG corresponding to 200 mg/dL (to convert to millimoles per liter, multiply by 0.0113), and total cholesterol, LDL-C, and HDL-C corresponding to 240, 160, and 40 mg/dL, respectively (to convert to millimoles per liter, multiply by 0.0259). The Common Terminology Criteria for Adverse Events reference ranges11 were used to define grade 2 or significant laboratory changes for the hepatic panel including AP, AST, and ALT corresponding to 367.5 U/L, 108 U/L, and 111 U/L, respectively (to convert to microkatals per liter, multiply by 0.0167).

Statistical Analysis

Trials reported findings from different laboratory studies and at varying intervals of repeated measurements in time. The 99% CI for each laboratory test in each study was calculated based on the reported mean (SD). The meta-analytic method used weighted means (SEs) to estimate the mean and 99% CI for the pool of participants. Midtreatment and late effects of isotretinoin therapy on laboratory results were analyzed whenever possible depending on the data available in published studies. Midtreatment was defined as 6 to 8 weeks of therapy. Late effects of prolonged isotretinoin therapy were examined for 16 to 20 weeks. A random effects model was used and statistical heterogeneity was quantified using the I2 and τ2 statistics. An assessment of the quality of the evidence was not performed. Data were analyzed from August 25, 2014, to December 4, 2015, using Stata, version 13 (StataCorp) and Comprehensive Meta-analyses software (Biostat Inc).

Results

The initial search identified 342 references (Figure 1); 116 of these (33.9%) were selected for full-text examination. The meta-analysis of changes in laboratory values included 22 randomized clinical trials and 4 retrospective studies1,7,12,13 with a total of 1574 participants. The individual studies are described in eTable 1 in the Supplement. Seven of these studies reported discontinuation rates for subjects owing to laboratory abnormalities, which ranged from 0.71% (1 of 140)7,12 to 22.5% (9 of 40),14 with a mean (SD) of 4.4 (6.9) (eTable 2 in the Supplement). There were 25 randomized clinical trials and 10 retrospective studies with a total of 17 915 participants that lacked data on laboratory values, which are summarized below in a narrative review. The excluded references are listed in eTable 3 in the Supplement.

Lipid Panel
Triglycerides

The mean value of nonbaseline measurements 15-33(Figure 2A) or those made during isotretinoin therapy was 119.98 mg/dL (99% CI, 98.58-141.39 mg/dL). The difference in mean values between baseline and the mean follow-up period (11.3 weeks) (Figure 2B) was 36.96 mg/dL (99% CI, 22.12-51.79 mg/dL).

To examine midtreatment and later effects of isotretinoin therapy, the difference in means between baseline and 8 weeks and 20 weeks (eFigure 1A and B in the Supplement) was examined. For 8 weeks, the difference from baseline was 45.32 mg/dL (99% CI, 22.73-67.92 mg/dL), and for 20 weeks, the difference from baseline was 45.63 mg/dL (99% CI, 5.15-80.11 mg/dL). The 2 analyses consisted of different studies because not all studies reported values for all time points. However, the change in TG levels from baseline to 8 weeks and 20 weeks does not demonstrate a substantial late effect of isotretinoin therapy.

Total Cholesterol

The mean value of nonbaseline measurements (Figure 3A) or those made during isotretinoin therapy was 184.74 mg/dL (99% CI, 178.17-191.31 mg/dL). All but one study reported all observations as within the reference range. In one study13 the 99% CI extended above 240 mg/dL, with a mean of 235.90 mg/dL (99% CI, 206.02-265.78 mg/dL). The difference in mean values between baseline and the mean follow-up period (11.1 weeks) (Figure 3B) was 19.73 mg/dL (99% CI, 16.00-23.47 mg/dL). In 3 studies,19,21,24 there were patients who had a change in total cholesterol of up to 60 mg/dL. At 16 weeks (eFigure 2A in the Supplement), the difference from baseline was 23.51 mg/dL (99% CI, 16.84-30.18 mg/dL), and for 20 weeks (eFigure 2B in the Supplement), the difference was 17.72 mg/dL (99% CI, 6.83-28.61 mg/dL). The 2 analyses consisted of different studies because not all studies reported values for all time points. However, the change in total cholesterol from baseline to 16 weeks and 20 weeks did not demonstrate a substantial late effect of isotretinoin therapy.

Low-Density Lipoprotein Cholesterol

The mean value of nonbaseline measurements or those made during isotretinoin therapy was 109.23 mg/dL (99% CI, 103.68-114.79 mg/dL). The difference in mean values between baseline and the mean follow-up period (9.7 weeks) was 16.08 mg/dL (99% CI, 13.37-18.78 mg/dL) (eFigure 3A and B in the Supplement). Analyses for late effects could not be made because of lack of available data.

High-Density Lipoprotein Cholesterol

The mean value of nonbaseline measurements or those made during isotretinoin therapy was 42.80 mg/dL (99% CI, 39.84 to 45.76 mg/dL). The difference in mean values between baseline and the mean follow-up period (9.1 weeks) was −4.82 mg/dL (99% CI, −6.72 to −2.92 mg/dL) (eFigure 3C and D in the Supplement). Analyses for late effects could not be made because of a lack of available data in the studies.

Hepatic Panel
Aspartate Aminotransferase

The mean value of nonbaseline measurements (Figure 4A) or those made during isotretinoin therapy was 22.67 U/L (99% CI, 19.94-25.41 U/L). The difference in mean values between baseline and the mean follow-up period (6.6 weeks) (Figure 4B) was 3.72 U/L (99% CI, 2.44-5.01 U/L). Analyses for late effects could not be made because of a lack of available data. To examine midtreatment effects of isotretinoin therapy, the difference in means between baseline and 6 weeks and 8 weeks (eFigure 4A and B in the Supplement) was examined. For 6 weeks, the difference from baseline was 4.52 U/L (99% CI, 2.91-6.13 U/L); for 8 weeks, the difference from baseline was 3.72 U/L (99% CI, 2.34-5.09 U/L). The 2 analyses consisted of different studies because not all studies reported values for all time points. However, the change in AST from baseline to 6 weeks and 8 weeks does not demonstrate a substantial midtreatment effect of isotretinoin therapy.

Alanine Aminotransferase

The mean value of nonbaseline measurements (Figure 5A) or those made during isotretinoin therapy was 21.77 U/L (99% CI, 18.96-24.59 U/L). The difference in mean values between baseline and the mean follow-up period (6.5 weeks) (Figure 5B) was 3.22 U/L (99% CI, 0.99-5.45 U/L). Analyses for late effects could not be made because of a lack of available data.

Alkaline Phosphatase

The mean value of nonbaseline measurements (eFigure 5A in the Supplement) or those made during isotretinoin therapy was 88.35 U/L (99% CI, 58.94-117.76 U/L). The difference in mean values between baseline and the mean follow-up period (6.6 weeks) (eFigure 5B in the Supplement) was 4.23 U/L (99% CI, 0.70-7.76 U/L). Analyses for late effects could not be made because of a lack of available data.

Complete Blood Cell Count

Analyses of hemoglobin, hematocrit, and platelet counts were not performed because of a lack of data. The mean value of nonbaseline measurements of the white blood cell count or those made during isotretinoin therapy was 6890/µL (99% CI, 5700/µL to 8030/µL). The difference in mean values between baseline and the mean follow-up period (11.5 weeks) was −1130/µL (99% CI, −2140/µL to −110/µL) (eFigure 6 in the Supplement). Analyses for late effects could not be made because of a lack of available data.

Narrative Summary of Remaining Studies
Lipid Panel

Thirty-five studies were included in the qualitative analysis (Figure 1). A subset of studies reported no significant elevations in total cholesterol,34-37 TG,35,37-39 HDL-C,40-42 and LDL-C levels41 but did not report specific laboratory values. Several studies reported measurable increases in serum lipids43-45 but did not include details on the lipid type.

Triglyceride level elevations were reported, including increases above 200 mg/dL in 5.0% (20 of 400),46 8.7% (41 of 473, with 3 [0.6%] discontinuing treatment),47 35.9% (75 of 209),6 and 8.3% (5 of 60)48 of the patients; above 300 mg/dL in 10.0% (1 of 10)49 and 4.3% (4 of 94)50 of the patients; and above 400 mg/dL in 1.5% (14 of 907),5 3.3% (7 of 209),6 and 10.0% (1 of 10)49 of the patients. Other studies reported significant increases in 12.1% (7 of 58)51 and 35.8% (19 of 53)52 of the patients but did not specify the threshold value.

Kaymak and Ilter53 reported elevated TG levels between the fourth and eighth week in 22.0% (22 of 100) of the patients. Sixteen percent (16 of 100) had a TG level of 210 to 350 mg/dL, but 1.0% (1 of 100) had a TG level greater than 730 mg/dL at the fourth month, which decreased with a lowered dosage. Cyrulnik et al54 reported that 18.8% (15 of 80) of the patients had elevated TG levels, with 12.5% (10 of 80) between 150 and 375 mg/dL and 6.3% (5 of 80) between 376 and 750 mg/dL. Zane et al3 reported that 44.0% (4231 of 9620) of the patients with normal baseline TG levels had an elevation during treatment: 40.4% (3882) had mild elevations (150-375 mg/dL) and 3.6% (349) had transient and reversible moderate to severe elevations (>375 mg/dL).

Elevated total cholesterol levels above the high-risk threshold (240 mg/dL) were reported in 3.2% (3 of 94),50 13.8% (55 of 400),46 18.2% (4 of 22),55 5.0% (5 of 100),53 3.2% (2 of 63),48 and 10.5% (22 of 209)6 of the patients; elevations above 300 mg/dL were reported in 0.6% (5 of 907)5 and 1.4% (135 of 9641) (with 0.1% [19] abnormal at baseline)3 of the patients. For patients with normal values at baseline testing, Zane et al3 reported mild elevations (201-300 mg/dL) in 31.2% (2283 of 7325) and severe elevations (≥301 mg/dL) in 0.1% (9 of 7325) of the patients. Kaymak and Ilter53 reported elevated total cholesterol levels (278-372 mg/dL) in 5.0% (5 of 100) of the patients. Two studies reported elevated total cholesterol levels in 8.9% (4 of 45)56 and 7.5% (4 of 53)52 of the patients but did not define the threshold value.

Studies reported abnormal HDL-C levels in 42.0% (58 of 138)57 and 20.0% (2 of 10) of the patients.49 A few studies commented on a significant40,42,58,59 or slight60 increase in total cholesterol levels, significant42,58,59 or slight34 increase in TG levels, significant increase in LDL-C levels,42,59 and significant decrease in HDL-C levels59 but did not provide more specific data.

Liver Function Tests

Many studies reported no significant elevations in any of the liver function tests during treatment.17,18,35,37-39,42,60,61 Several other studies reported no elevations in individual components including ALT,42,44 AST,6,42,44 or AP levels.6,15,22,34,51 Two studies25,43 mentioned that a “liver panel” was performed, and 4 reported that AP levels were determined,44,49,52,53 but specific information was missing.

Moderate or higher elevations in liver function tests were reported in 2 studies,3,62 but the thresholds were not consistently defined, so they may not agree with the Common Terminology Criteria for Adverse Events reference ranges. Zane et al3 described moderate elevations (>101 U/L) in either AST or ALT levels in 1.5% (179 of 11 676) of the patients; in comparison, 0.4% (49 of 12 503) had a moderate abnormality at baseline. McElwee et al62 reported moderate elevations in 1.8% (6 of 341) of the patients without baseline abnormalities (0.9% [3] discontinued the medication). One patient (0.3%) with an elevated baseline AST level had a transient rise to 7 times the upper limit of normal, but treatment was not discontinued. Two studies reported a small percentage of patients who withdrew owing to elevations in ALT or AST levels. Strauss et al25 reported 3.1% (9 of 295) of the patients withdrew owing to elevated TG, ALT, or AST levels, and Ertam et al42 indicated that 1.1% (1 of 91) of the patients discontinued therapy owing to increased ALT or AST levels; the exact value was not reported.

Several studies reported elevations in liver function tests without specific values. Four studies did not specify the component (ALT, AST, or AP) but reported an increase in 3.8% (3 of 78),45 17.8% (8 of 45),56 2.4% (3 of 127),63 6.0% (6 of 100),53 and 3.7% (1 of 27)44 of the patients. Other studies reported elevations in ALT in 7.9% (18 of 228),57 2.1% (2 of 94),50 2.5% (10 of 400),46 and 24.5% (13 of 53)52 of the patients; AST elevation in 7.0% (16 of 228)57 and 6.3% (25 of 400)46 of the patients; and AP elevation in 3.4% (7 of 206)57 of the patients. No patients in any of the above studies required a reduction in isotretinoin dose or discontinuation of therapy.

Discussion

This study was performed with the intent to shed more light on laboratory monitoring for isotretinoin therapy since there are major differences between the suggestions in the package insert and multiple studies that suggest less frequent testing.5-7 This meta-analysis showed that (1) isotretinoin is associated with a statistically significant change in the mean value of several laboratory tests (white blood cell count and hepatic and lipid panels), yet (2) the mean changes across a patient group did not meet a priori criteria for high-risk and (3) the proportion of patients with laboratory abnormalities was low.

All of the 99% CIs calculated in the meta-analyses showed a change from baseline; however, none of the intervals crossed the predefined thresholds for high-risk or grade 2 abnormalities. This finding indicated that 0.5% of patients, similar in characteristics and treatment to study participants, are expected to have a test result above or below the boundaries of the 99% CI. The results of the narrative review also indicated that laboratory changes are frequent, especially in TG and total cholesterol levels, yet high-risk or severe abnormalities are infrequent. The meta-analysis determined that changes in total cholesterol and TG levels were similar alterations from baseline to 8 weeks or 20 weeks. These findings support the suggestions by Barth et al6 and Altman et al7 to perform laboratory monitoring at baseline and during the first 1 to 2 months of isotretinoin therapy rather than continue monitoring throughout the course of treatment.

The results of this study should be considered in the context of its limitations. The meta-analysis is limited by the availability of extant data and the completeness of the reports. We did not have access to information about the patients or the treatment, so associations between isotretinoin doses or dose changes could not be correlated with specific laboratory abnormalities. Similarly, we were not able to investigate the fasting or nonfasting status of patients at the time of testing and correlation with laboratory results since these data were limited.

The findings of this study suggest that less frequent laboratory monitoring may be safe, with few missed high-risk laboratory changes, for many patients with acne who are receiving typical doses of isotretinoin. Clinical judgment should be used to determine monitoring frequency for each patient based on baseline laboratory findings and concomitant conditions, such as preexisting liver disease, concomitant use of hepatotoxic medications, or metabolic syndrome, which may increase the risk of laboratory abnormalities.

Conclusions

The results of this study do not support the use of monthly laboratory tests for all patients with acne who receive standard doses of isotretinoin. A decrease in the frequency of laboratory monitoring for some patients could help to decrease health care spending and potential anxiety-provoking blood sampling. At our institution, we perform a lipid and hepatic panel at baseline and after 2 months of isotretinoin treatment, with more frequent monitoring dictated by baseline abnormalities and medical history. Further studies may be needed to investigate the influence of patient characteristics, which may allow risk stratification and, subsequently, clinically indicated and cost-efficient monitoring.

Article Information

Correction: This article was corrected on January 13, 2016, to fix the first author’s affiliation.

Corresponding Author: Joslyn S. Kirby, MD, MEd, MS, Department of Dermatology, Penn State Milton S. Hershey Medical Center, 500 University Ave, HU 14, Hershey, PA 17033 (jkirby1@hmc.psu.edu).

Accepted for Publication: July 23, 2015.

Published Online: December 2, 2015. doi:10.1001/jamadermatol.2015.3091.

Author Contributions: Drs Lee and Kirby had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Lee.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Lee, Scharnitz, Chen, Gupta-Elera, Kirby.

Critical revision of the manuscript for important intellectual content: Lee, Scharnitz, Muscat.

Statistical analysis: Lee, Scharnitz, Muscat, Chen, Gupta-Elera.

Obtained funding: Lee, Kirby.

Administrative, technical, or material support: Kirby.

Study supervision: Kirby.

Conflict of Interest Disclosures: None reported.

Funding/Support: This study was supported by grant 106485 from the American Acne and Rosacea Society.

Role of the Funder/Sponsor: The funding organization had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Previous Presentation: Parts of this work were presented as an abstract at the Society for Investigative Dermatology Annual Meeting; May 7, 2015; Atlanta, Georgia.

References
1.
Vieira  AS, Beijamini  V, Melchiors  AC.  The effect of isotretinoin on triglycerides and liver aminotransferases.  An Bras Dermatol. 2012;87(3):382-387.PubMedGoogle ScholarCrossref
2.
Flynn  WJ, Freeman  PG, Wickboldt  LG.  Pancreatitis associated with isotretinoin-induced hypertriglyceridemia.  Ann Intern Med. 1987;107(1):63.PubMedGoogle ScholarCrossref
3.
Zane  LT, Leyden  WA, Marqueling  AL, Manos  MM.  A population-based analysis of laboratory abnormalities during isotretinoin therapy for acne vulgaris.  Arch Dermatol. 2006;142(8):1016-1022.PubMedGoogle ScholarCrossref
4.
Roche Laboratories. Accutane (isotretinoin capsules). http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/018662s059lbl.pdf. Published November 2008. Accessed July 5, 2014.
5.
Alcalay  J, Landau  M, Zucker  A.  Analysis of laboratory data in acne patients treated with isotretinoin: is there really a need to perform routine laboratory tests?  J Dermatolog Treat. 2001;12(1):9-12.PubMedGoogle ScholarCrossref
6.
Barth  JH, Macdonald-Hull  SP, Mark  J, Jones  RG, Cunliffe  WJ.  Isotretinoin therapy for acne vulgaris: a re-evaluation of the need for measurements of plasma lipids and liver function tests.  Br J Dermatol. 1993;129(6):704-707.PubMedGoogle ScholarCrossref
7.
Altman  RS, Altman  LJ, Altman  JS.  A proposed set of new guidelines for routine blood tests during isotretinoin therapy for acne vulgaris.  Dermatology. 2002;204(3):232-235.PubMedGoogle ScholarCrossref
8.
Hansen  T, Zaenglein  A, Miller  J.  Standardizing laboratory monitoring of patients undergoing isotretinoin treatment using a cost-effective and best evidence approach [abstract].  J Am Acad Dermatol. 2013;68(4)(suppl 1):AB6.Google Scholar
9.
University of York Centres for Reviews and Dissemination.  PROSPERO database: laboratory monitoring during treatment with isotretinoin. Registration CRD42014010494. http://www.crd.york.ac.uk/prospero. Accessed July 3, 2014.
10.
National Institutes of Health.  Clinical Center Test Guide: Lipid Panel. Washington, DC: US Dept of Health and Human Services; 2015.
11.
National Institutes of Health.  Clinical Center Test Guide: Hepatic Panel. Washington, DC: US Dept of Health and Human Services; 2015.
12.
Ragos  G, Houlden  R, Danby  FW.  Effect of isotretinoin therapy on serum total cholesterol and triglycerides.  Can J Clin Pharmacol. 1998;5(1):43-47.Google Scholar
13.
Buckley  D, Rogers  S, Daly  P.  Isotretinoin therapy for acne vulgaris: results in an Irish population.  Ir J Med Sci. 1990;159(1):2-5.PubMedGoogle ScholarCrossref
14.
Erturan  İ, Naziroğlu  M, Akkaya  VB.  Isotretinoin treatment induces oxidative toxicity in blood of patients with acne vulgaris: a clinical pilot study.  Cell Biochem Funct. 2012;30(7):552-557.PubMedGoogle ScholarCrossref
15.
Michaëlsson  G, Vahlquist  A, Mobacken  H,  et al.  Changes in laboratory variables induced by isotretinoin treatment of acne.  Acta Derm Venereol. 1986;66(2):144-148.PubMedGoogle Scholar
16.
Bershad  S, Rubinstein  A, Paterniti  JR,  et al.  Changes in plasma lipids and lipoproteins during isotretinoin therapy for acne.  N Engl J Med. 1985;313(16):981-985.PubMedGoogle ScholarCrossref
17.
Hanstad  IK, Thune  P.  Nodulocystic acne: treatment with isotretinoin (Roaccutan)—quantitative measures of skin lipids [in Norwegian].  Tidsskr Nor Laegeforen. 1985;105(23):1497-1500.PubMedGoogle Scholar
18.
Pigatto  PD, Finzi  AF, Altomare  GF, Polenghi  MM, Vergani  C, Vigotti  G.  Isotretinoin versus minocycline in cystic acne: a study of lipid metabolism.  Dermatologica. 1986;172(3):154-159.PubMedGoogle ScholarCrossref
19.
Laker  MF, Green  C, Bhuiyan  AK, Shuster  S.  Isotretinoin and serum lipids: studies on fatty acid, apolipoprotein and intermediary metabolism.  Br J Dermatol. 1987;117(2):203-206.PubMedGoogle ScholarCrossref
20.
Melnik  B, Bros  U, Plewig  G.  Characterization of apoprotein metabolism and atherogenic lipoproteins during oral isotretinoin treatment.  Dermatologica. 1987;175(suppl 1):158-168.PubMedGoogle ScholarCrossref
21.
Lyons  F, Laker  MF, Marsden  JR, Manuel  R, Shuster  S.  Effect of oral 13-cis-retinoic acid on serum lipids.  Br J Dermatol. 1982;107(5):591-595.PubMedGoogle ScholarCrossref
22.
Jones  DH, King  K, Miller  AJ, Cunliffe  WJ.  A dose-response study of I3-cis-retinoic acid in acne vulgaris.  Br J Dermatol. 1983;108(3):333-343.PubMedGoogle ScholarCrossref
23.
Strauss  JS, Rapini  RP, Shalita  AR,  et al.  Isotretinoin therapy for acne: results of a multicenter dose-response study.  J Am Acad Dermatol. 1984;10(3):490-496.PubMedGoogle ScholarCrossref
24.
Ostlere  LS, Harris  D, Morse-Fisher  N, Wright  S.  Effect of systemic administration of isotretinoin on blood lipids and fatty acids in acne patients.  Int J Dermatol. 1996;35(3):216-218.PubMedGoogle ScholarCrossref
25.
Strauss  JS, Leyden  JJ, Lucky  AW,  et al.  Safety of a new micronized formulation of isotretinoin in patients with severe recalcitrant nodular acne: a randomized trial comparing micronized isotretinoin with standard isotretinoin.  J Am Acad Dermatol. 2001;45(2):196-207.PubMedGoogle ScholarCrossref
26.
Ferahbas  A, Turan  MT, Esel  E, Utas  S, Kutlugun  C, Kilic  CG.  A pilot study evaluating anxiety and depressive scores in acne patients treated with isotretinoin.  J Dermatolog Treat. 2004;15(3):153-157.PubMedGoogle ScholarCrossref
27.
Koistinen  HA, Remitz  A, Koivisto  VA, Ebeling  P.  Paradoxical rise in serum adiponectin concentration in the face of acid-induced insulin resistance 13-cis-retinoic.  Diabetologia. 2006;49(2):383-386.PubMedGoogle ScholarCrossref
28.
Polat  M, Lenk  N, Bingöl  S,  et al.  Plasma homocysteine level is elevated in patients on isotretinoin therapy for cystic acne: a prospective controlled study.  J Dermatolog Treat. 2008;19(4):229-232.PubMedGoogle ScholarCrossref
29.
Roodsari  MR, Akbari  MR, Sarrafi-rad  N, Saeedi  M, Gheisari  M, Kavand  S.  The effect of isotretinoin treatment on plasma homocysteine levels in acne vulgaris.  Clin Exp Dermatol. 2010;35(6):624-626.PubMedGoogle ScholarCrossref
30.
Ertugrul  DT, Karadag  AS, Tutal  E, Akin  KO.  Isotretinoin does not induce insulin resistance in patients with acne.  Clin Exp Dermatol. 2011;36(2):124-128.PubMedGoogle ScholarCrossref
31.
Dursun  R, Alpaslan  M, Caliskan  M,  et al.  Isotretinoin does not prolong QT intervals and QT dispersion in patients with severe acne: a surprising finding for a drug with numerous side effects.  J Drugs Dermatol. 2011;10(7):710-714.PubMedGoogle Scholar
32.
Karadag  AS, Tutal  E, Ertugrul  DT, Akin  KO.  Effect of isotretinoin treatment on plasma holotranscobalamin, vitamin B12, folic acid, and homocysteine levels: non-controlled study.  Int J Dermatol. 2011;50(12):1564-1569.PubMedGoogle ScholarCrossref
33.
Koistinen  HA, Remitz  A, Gylling  H, Miettinen  TA, Koivisto  VA, Ebeling  P.  Dyslipidemia and a reversible decrease in insulin sensitivity induced by therapy with 13-cis-retinoic acid.  Diabetes Metab Res Rev. 2001;17(5):391-395.PubMedGoogle ScholarCrossref
34.
Rødland  O, Aksnes  L, Nilsen  A, Morken  T.  Serum levels of vitamin D metabolites in isotretinoin-treated acne patients.  Acta Derm Venereol. 1992;72(3):217-219.PubMedGoogle Scholar
35.
Hoting  VE, Schütte  B, Schirren  C.  Isotretinoin treatment of acne conglobate: andrologic follow-up [in German].  Fortschr Med. 1992;110(23):427-430.PubMedGoogle Scholar
36.
Bruhat  MA, Mage  G, Manhes  H, Pouly  JL, Jacquetin  B.  The indication for laparoscopy in female infertility [in French].  J Gynecol Obstet Biol Reprod (Paris). 1980;9(3):337-340.PubMedGoogle Scholar
37.
Meigel  W, Gollnick  H, Wokalek  H, Plewig  G.  Oral treatment of acne conglobata using 13-cis-retinoic acid: results of the German multicentric study following 24 weeks of treatment [in German].  Hautarzt. 1983;34(8):387-397.PubMedGoogle Scholar
38.
Plewig  G, Gollnick  H, Meigel  W, Wokalek  H.  13-Cis retinoic acid in the oral therapy of acne conglobate: results of a multi-center study [in German].  Hautarzt. 1981;32(12):634-646.PubMedGoogle Scholar
39.
Wagner  A, Plewig  G.  13-Cis-retinoic acid: pharmacologic and toxicologic findings in treatment of severe forms of acne [in German].  MMW Munch Med Wochenschr. 1980;122(38):1294-1300.PubMedGoogle Scholar
40.
Effects of isotretinoin on plasma lipids and lipoproteins.  Nutr Rev. 1986;44(6):196-198.PubMedGoogle Scholar
41.
Zech  LA, Gross  EG, Peck  GL, Brewer  HB.  Changes in plasma cholesterol and triglyceride levels after treatment with oral isotretinoin: a prospective study.  Arch Dermatol. 1983;119(12):987-993.PubMedGoogle ScholarCrossref
42.
Ertam  I, Alper  S, Unal  I.  Is it necessary to have routine blood tests in patients treated with isotretinoin?  J Dermatolog Treat. 2006;17(4):214-216.PubMedGoogle ScholarCrossref
43.
Wahab  R, Rahman  M, Monamie  N, Jamaluddin  M, Khondker  L, Afroz  W.  Isotretinoin vs weekly pulse dose azithromycin in the treatment of acne—a comparative study.  J Pak Assoc Dermatol. 2008;18:9-14.Google Scholar
44.
Agarwal  US, Besarwal  RK, Bhola  K.  Oral isotretinoin in different dose regimens for acne vulgaris: a randomized comparative trial.  Indian J Dermatol Venereol Leprol. 2011;77(6):688-694.PubMedGoogle ScholarCrossref
45.
Ahmed  I, Wahid  Z, Nasreen  S.  Adverse effects of systemic isotretinoin therapy: a study of 78 patients.  J Pak Assoc Dermatol. 2005;15:242-246.Google Scholar
46.
Tallab  T, Joharji  H, Jazei  M, Bahamdan  K, Ibrahim  K, Karkashan  E.  Isotretinoin therapy: any need for laboratory assessment?  West Afr J Med. 2004;23(4):273-275.PubMedGoogle Scholar
47.
Sadick  NA.  Practitioner’s 10-year experience with isotretinoin and side effect profiles.  Int J Cosmet Surg Aesthetic Dermatol. 2002;4(2):89-94.Google ScholarCrossref
48.
Ng  PP, Goh  CL.  Treatment outcome of acne vulgaris with oral isotretinoin in 89 patients.  Int J Dermatol. 1999;38(3):213-216.PubMedGoogle ScholarCrossref
49.
Spear  KL, Muller  SA.  Treatment of cystic acne with 13-cis-retinoic acid.  Mayo Clin Proc. 1983;58(8):509-514.PubMedGoogle Scholar
50.
Hermes  B, Praetel  C, Henz  BM.  Medium dose isotretinoin for the treatment of acne.  J Eur Acad Dermatol Venereol. 1998;11(2):117-121.PubMedGoogle ScholarCrossref
51.
van der Meeren  HL, van der Schroeff  JG, Stijnen  T, van Duren  JA, van der Dries  HA, van Voorst Vader  PC.  Dose-response relationship in isotretinoin therapy for conglobate acne.  Dermatologica. 1983;167(6):299-303.PubMedGoogle ScholarCrossref
52.
Shahidullah  M, Tham  SN, Goh  CL.  Isotretinoin therapy in acne vulgaris: a 10-year retrospective study in Singapore.  Int J Dermatol. 1994;33(1):60-63.PubMedGoogle ScholarCrossref
53.
Kaymak  Y, Ilter  N.  The results and side effects of systemic isotretinoin treatment in 100 patients with acne vulgaris.  Dermatol Nurs. 2006;18(6):576-580.PubMedGoogle Scholar
54.
Cyrulnik  AA, Viola  KV, Gewirtzman  AJ, Cohen  SR.  High-dose isotretinoin in acne vulgaris: improved treatment outcomes and quality of life.  Int J Dermatol. 2012;51(9):1123-1130.PubMedGoogle ScholarCrossref
55.
Gandola  M.  Therapy of severe acne and acne rosacea with oral 13-cis-retinoic acid (isotretinoin) [in Italian].  Acta Vitaminol Enzymol. 1984;6(4):325-337.PubMedGoogle Scholar
56.
Bruno  NP, Beacham  BE, Burnett  JW.  Adverse effects of isotretinoin therapy.  Cutis. 1984;33(5):484-486, 489.PubMedGoogle Scholar
57.
Entezari-Maleki  T, Hadjibabaeil  M, Salamzadeh  J, Javadil  MR, Shalviri  G, Gholamil  K.  Evaluation and monitoring of isotretinoin use in Iran.  Arch Iran Med. 2012;15(7):409-412.Google Scholar
58.
Gollnick  H, Luley  C, Schwartzkopff  W, Orfanos  CE.  Changes in serum lipid fractions as a side effect of oral retinoids [in German].  Z Hautkr. 1982;57(17):1255-1267.PubMedGoogle Scholar
59.
O’Leary  TJ, Simo  IE, Kanigsberg  N, Walker  J, Goodall  JC, Ooi  TC.  Changes in serum lipoproteins and high-density lipoprotein composition during isotretinoin therapy.  Clin Invest Med. 1987;10(4):355-360.PubMedGoogle Scholar
60.
Amblard  P, Beani  JC, Reymond  JL, Didier  B, Coignet  M.  Our experience of isotretinoin in the treatment of severe acne for about 421 treated patients [in French].  Sem Hop Ther Paris. 1986;62(1-2):61-66.Google Scholar
61.
Almond-Roesler  B, Blume-Peytavi  U, Bisson  S, Krahn  M, Rohloff  E, Orfanos  CE.  Monitoring of isotretinoin therapy by measuring the plasma levels of isotretinoin and 4-oxo-isotretinoin: a useful tool for management of severe acne.  Dermatology. 1998;196(1):176-181.PubMedGoogle ScholarCrossref
62.
McElwee  NE, Schumacher  MC, Johnson  SC,  et al.  An observational study of isotretinoin recipients treated for acne in a health maintenance organization.  Arch Dermatol. 1991;127(3):341-346.PubMedGoogle ScholarCrossref
63.
Al-Mutairi  N, Manchanda  Y, Nour-Eldin  O, Sultan  A.  Isotretinoin in acne vulgaris: a prospective analysis of 160 cases from Kuwait.  J Drugs Dermatol. 2005;4(3):369-373.PubMedGoogle Scholar