Severe And Persistent Thyroid Dysfunction Associated With Tetracycline-Antibiotic Treatment In Youth

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  1. Tristan Loscha

    Tristan Loscha Member

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    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4884496/

    J Pediatr
    . Author manuscript; available in PMC 2017 Jun 1.
    Published in final edited form as:
    J Pediatr. 2016 Jun; 173: 232–234.
    Published online 2016 Apr 5. doi: 10.1016/j.jpeds.2016.03.034
    PMCID: PMC4884496
    NIHMSID: NIHMS770861
    PMID: 27059913
    Severe and persistent thyroid dysfunction associated with tetracycline-antibiotic treatment in youth
    Allison J Pollock, MD,1 Tasa Seibert, MD MPH,2 and David B Allen, MD1
    Author information Copyright and License information Disclaimer
    The publisher's final edited version of this article is available at J Pediatr
    See other articles in PMC that cite the published article.
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    Abstract
    Thyroid dysfunction in adolescents treated with minocycline for acne has been previously described as transient effect and/or associated with autoimmune thyroiditis. We report non-immune-mediated thyroid dysfunction associated with minocycline/doxycycline in three adolescents whose clinical courses suggest an adverse effect that may be more common, serious, and persistent than realized previously.

    Keywords: minocycline, thyroiditis, tetracycline, doxycycline, hyperthyroidism, hypothyroidism, acne vulgaris, thyroid dysfunction









    J Pediatr. Author manuscript; available in PMC 2017 Jun 1.
    Published in final edited form as:
    J Pediatr. 2016 Jun; 173: 232–234.
    Published online 2016 Apr 5. doi: 10.1016/j.jpeds.2016.03.034
    PMCID: PMC4884496
    NIHMSID: NIHMS770861
    PMID: 27059913
    Severe and persistent thyroid dysfunction associated with tetracycline-antibiotic treatment in youth
    Allison J Pollock, MD,1 Tasa Seibert, MD MPH,2 and David B Allen, MD1
    Author information Copyright and License information Disclaimer
    The publisher's final edited version of this article is available at J Pediatr
    See other articles in PMC that cite the published article.
    Go to:
    Abstract
    Thyroid dysfunction in adolescents treated with minocycline for acne has been previously described as transient effect and/or associated with autoimmune thyroiditis. We report non-immune-mediated thyroid dysfunction associated with minocycline/doxycycline in three adolescents whose clinical courses suggest an adverse effect that may be more common, serious, and persistent than realized previously.

    Keywords: minocycline, thyroiditis, tetracycline, doxycycline, hyperthyroidism, hypothyroidism, acne vulgaris, thyroid dysfunction
    Tetracycline antibiotics, including minocycline and doxycycline, are prescribed commonly for adolescents to treat acne vulgaris. An association of tetracycline-class antibiotic treatment with thyroid abnormalities was first reported in 1976, when the autopsy of a 69-year-old man treated with minocycline revealed black pigmentation of the thyroid grossly, pigment aggregates in follicular cells and colloid, interstitial fibrosis, and pyknotic nuclei suggesting epithelial damage.1 The association with black pigmentation without alteration in thyroid gland function has been firmly established by autopsy studies.24 In contrast, thyroid dysfunction due to tetracycline-class drugs is rarely reported in adults and only two cases of minocycline-induced thyroid dysfunction have been described in the pediatric population. In both of these cases, thyroid dysfunction was associated with concomitant autoimmune thyroiditis5 or other autoimmunity.6 Severity of thyroid dysfunction was mild and transient in one case and impossible to evaluate in the other due to definitive treatment with thyroid ablation. In contrast, we report three pediatric patients treated with tetracycline-class antibiotics who developed non-immune-mediated thyroid dysfunction that was severe and/or persistent.

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    Methods
    Cases were selected from the electronic medical record. Inclusion criteria: Patients aged <18 years evaluated by pediatric endocrinologists at the University of Wisconsin Hospital and Clinics between 2000–2014 who had an abnormal TSH (thyroid stimulating hormone) result coinciding temporally with tetracycline-class drug prescription. Exclusion criteria: autoimmune thyroid disease, congenital thyroid disease, thyroid cancer, and sick euthyroid syndrome.

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    Results
    Twenty-one patients met inclusion criteria. Of these, 17 were excluded due to autoimmune thyroid disease (n=14), congenital thyroid disease (n=1), thyroid cancer (n=1), and sick euthyroid syndrome (n=1). Four patients remained; one was removed due to potentially confounding valproate therapy for seizures. The remaining three patients all had acne vulgaris and came to attention at 16 years of age with hyperthyroidism, negative anti-thyroid antibodies, and low uptake on radioiodine thyroid uptake scan.

    Case 1
    A 16-year-old female developed diplopia, headache and fatigue 3 months after starting oral doxycycline for treatment of acne vulgaris. Free T4 (free thyroxine) was elevated (2.1 ng/dL (reference range 0.9–1.7 ng/dL), thyrotropin suppressed (0.009; reference range 0.500–5.500 μIU/mL) and thyroid scan showed low uptake (2.9%; reference range 10%-35%). TPO (thyroid peroxidase), TSI (thyroid stimulating immunoglobulin) and thyroglobulin antibodies were negative. There was no known family history of thyroid or autoimmune disease. Doxycycline was discontinued and hyperthyroidism resolved.

    Case 2
    A 16.5-year-old male developed polydipsia, headache, weight loss and fatigue 23 months after starting oral minocycline therapy for treatment of acne vulgaris. Free T4 was elevated (7.57 ng/dl ; reference range 0.75–1.54), thyrotropin was suppressed (<0.03 μIU/mL; reference range 0.36–4.57), and thyroid scan showed low uptake (0.30%; reference range 10–35%). TPO, TSI, TRAb (TSH receptor antibodies), thyroglobulin antibodies were negative. Mother had a benign thyroid nodule and the maternal grandmother had celiac disease and multiple sclerosis. Minocycline was discontinued and hyperthyroidism was treated with propranolol and methimazole for 1 month. He experienced transient compensated hypothyroidism (TSH 7.56 μIU/mL; reference range 0.36–4.57) and then thyroid function normalized.

    Case 3
    A 16.2-year-old male developed polydipsia, headache, night sweats and fatigue 9 months after starting oral minocycline therapy for treatment of acne vulgaris. Free T4 was elevated (3.26 ng/dL; reference range 0.70 – 1.45), TSH suppressed (0.01 μIU/ml; reference range 0.36 – 4.20), and thyroid scan showed low uptake (0.50%; reference range 10–35%). TPO, TSI, TRAb (TSH receptor antibodies), thyroglobulin antibodies were negative. A maternal aunt had a history of radioactive iodine ablation, but no other known family history of thyroid or autoimmune disease. Hyperthyroidism was initially treated with methimazole (5 days) and propranolol (1.5 months). Minocycline was discontinued. Hypothyroidism (TSH 19.3 μIU/ml; reference range 0.36 – 4.20) then developed and persists to the present (>4.5 years), treated with levothyroxine replacement 68.5mcg/day.

    Patients’ presentation, laboratory and imaging findings, treatment, and clinical course are summarized in the Table.

    Table 1
    Summary of three pediatric cases of tetracycline-induced hyperthyroidism without autoimmunity, one of which was severe and persistent.

    TETRACYCLINE-INDUCED
    THYROID DYSFUNCTION
    Mild Severe Severe & Persistent
    Age (yrs) / Sex
    16.0 / Female 16.5 / Male 16.2 / Male
    Tetracycline-class
    oral acne medication
    (Total mg/day) (minocycline, 200mg)#
    doxycycline, 150mg
    for 3 months minocycline, 200mg
    for 23 months minocycline, 200mg
    for 9 months
    Presentation Fatigue, headaches, weakness,
    decreased endurance, puffy
    eyes, diplopia Fatigue, headaches, polydipsia,
    heat intolerance, weight-loss,
    sleep difficulties, palpitations,
    frequent stools Fatigue, polydipsia, heat
    intolerance, night sweats,
    coordination difficulties
    Antibodies
    TPO, TSI, TRAb, Thyroglobulin Negative Negative Negative
    Evidence of
    Hyperthyroidism TSH 0.013 (nl 0.5–5.5 µIU/mL)
    free T4 2.4 (nl 0.9–1.7 ng/dL)
    total T3 2.53 (nl 0.8–1.6 ng/mL) TSH <0.03 (nl 0.36–4.57 µIU/mL)
    free T4 7.57 (nl 0.75–1.54 ng/dL)
    free T3 23.5 (nl 2.0–4.9 pg/mL) TSH 0.01 (nl 0.36–4.20 µIU/mL)
    free T4 3.26 (nl 0.7–1.45 ng/dL)
    free T3 15.5 (nl 2.3–4.8 pg/mL)
    Evidence of
    Subsequent Hypothyroidism TSH 3.04
    (nl 0.5–5.5 µIU/mL) TSH 7.56
    (nl 0.36–4.57 µIU/ml) TSH 19.3
    (nl 0.36–4.20 µIU/mL)
    Radioiodine thyroid uptake scan
    (nl 10–35%) 2.9% 0.30% 0.5%
    Treatment of Hyperthyroidism
    after drug cessation None Methimazole + propranolol Methimazole + propranolol
    Subsequent Hypothyroidism? No Yes, transient Yes, persistent
    Open in a separate window
    TPO: thyroid peroxidase antibody, TSI: thyroid stimulating immunoglobulin, TRAb: Thyroid Stimulating Hormone receptor antibody.

    #This patient recently switched from minocycline to doxycycline. Previous minocycline duration unknown.
    nl = normal reference range

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    Discussion
    Tetracycline, first marketed by Lederle Laboratories in 1953, was frequently prescribed for treatment of acne vulgaris. Due to clinical advantages over tetracycline (e.g. simpler dosing schedule and improved digestive tolerability)7 doxycycline (1967) and minocycline (1972) became preferred, although their own adverse effects include gastrointestinal symptoms, photosensitivity, and pigment accumulation in nails, skin, sclerae and teeth. In addition, minocycline can induce autoimmune conditions including systemic lupus erythematosus, autoimmune hepatitis and less commonly, serum sickness and vasculitis810; doxycycline also can induce autoimmune hepatitis.11

    Although black pigmentation of the thyroid appears to occur commonly with exposure to minocycline or doxycycline, thyroid dysfunction manifesting as hyper- or hypothyroidism has been reported rarely. Proposed mechanisms include (1) competitive inhibition of TPO-induced iodination of tyrosine moieties in thyroglobulin, (2) inhibition of TPO-catalyzed coupling of iodotyrosine residues, (3) cytotoxic damage to follicular cells leading to release of preformed thyroid hormone, (4) indirect or direct antibody-mediated destruction of follicular cells.6, 12, 13

    Proposed mechanisms of tetracycline-class drug-induced pigmentation accumulation include (1) degradation from drug interaction with lipofuscin, (2) oxidation of the drug, (3) interaction via TPO with tyrosine metabolism (needed for melanin and neuromelanin), and (4) lysosomal dysfunction.1416 Pigmentation seems to occur rapidly and is enduring.14 Although black discoloration often is considered pathognomonic for minocycline exposure, less common etiologies include cystic fibrosis, ochronosis, mucoviscidosis, ceroid storage disease, bruising, hemorrhage, hemochromatosis and effects of other drugs including doxepin, lithium, and tricyclic antidepressants (via lysosomal accumulation).1720

    One in vitro study of minocycline effects on thyroid hormone synthesis found that only the combined presence of minocycline and TPO led to black pigmentation changes as well as disruption of synthesis steps. Specifically, minocycline appeared to inhibit TPO-catalyzed iodination at a potency similar to or greater than13 the anti-thyroid drugs methimazole and propylthiouracil. Inhibition of iodination was dose-dependent; at low concentrations (25 μM), minocycline competitively inhibited of TPO-induced iodination, whereas at high concentrations (100uM), it acted reversibly to inhibit iodination independent of inactivation of TPO.

    The three cases described herein illustrate that minocycline and doxycycline can result in more severe thyroid dysfunction in children and adolescents than previously demonstrated. Prior pediatric cases have been associated with evidence of autoimmunity.5, 6 The second novel observation from our cases is that concurrent autoimmunity is not a necessary component of tetracycline-induced clinical and laboratory-evident thyroid dysfunction. Thus, thyroiditis from minocycline in these cases appears to be a non-autoimmune chemical thyroiditis resulting in cytotoxic damage sufficient to cause marked release of thyroid hormone and, in some cases, subsequent persistent hypothyroidism. That being said, this chart review also found that it is not uncommon for tetracycline-antibiotic treated adolescents to have evidence for autoimmune thyroid dysfunction. It is possible that family history of autoimmunity in two of the three cases could point to a latent familial predisposition without detectable autoimmunity in the individual.

    In spite of these potential clinically significant effects on thyroid function, a warning about thyroid dysfunction is not included in the package insert for doxycycline,21 and is mentioned only as “cases of abnormal thyroid function have been reported” for minocycline.22 Routine clinical and laboratory evaluation of thyroid function is not currently recommended when prescribing these medications for treatment of acne.

    Tetracycline antibiotic-induced thyroid dysfunction may be more common, serious, and persistent than previously realized and should be considered in the differential diagnosis for pediatric cases of antibody-negative thyroid dysfunction. Minocycline and doxycycline can cause a non-immune chemical thyroiditis leading to severe hyperthyroidism. Following removal of offending antibiotics, this chemical thyroiditis can evolve into persistent hypothyroidism. Although doxycycline and minocycline are commonly prescribed to youth for treatment of acne vulgaris, the frequency of non-autoimmune thyroiditis related to minocycline or doxycycline is unknown. It is likely that the majority of cases escape clinical detection and diagnosis and therefore prospective studies are needed to determine the prevalence, clinical significance and severity of cases. Additional investigation is needed to determine whether routine screening of thyroid function in youth receiving long-term treatment with these antibiotics is warranted.

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    Acknowledgments
    Funded by the National Institutes of Health (Postdoctoral Fellowship grant T32 DK077586-06A1).

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    Abbreviations
    TSH thyroid stimulating hormone
    TPO thyroid perioxidase
    TSI thyroid stimulating immunoglobulins
    Free T4 free thyroxine
    TRAb TSH receptor antibodies
    Go to:
    Footnotes
    Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.



    The authors declare no conflicts of interest.

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    References
    1. Attwood HD, Dennett X. A black thyroid and minocycline treatment. Br Med J. 1976;2:1109–1110. [PMC free article] [PubMed] [Google Scholar]
    2. Azuma N, Hashimoto N, Nishioka A, Sano H. Black thyroid. Intern Med. 2010;49:1835–1836. [PubMed] [Google Scholar]
    3. Hall AH, Bean SM. Minocycline-induced black thyroid. Diagn Cytopathol. 2010;38:579–680. [PubMed] [Google Scholar]
    4. Kandil E, Abdel Khalek M, Alabbas H, Daroca P, Thethi T, Friedlander P, et al. Black thyroid associated with thyroid carcinoma. Int J Endocrinol. 2010;2010:681647. [PMC free article] [PubMed] [Google Scholar]
    5. Brown RJ, Rother KI, Artman H, Mercurio MG, Wang R, Looney RJ, et al. Minocycline-induced drug hypersensitivity syndrome followed by multiple autoimmune sequelae. Arch Dermatol. 2009;145:63–66. [PMC free article] [PubMed] [Google Scholar]
    6. Benjamin RW, Calikoglu AS. Hyperthyroidism and lupus-like syndrome in an adolescent treated with minocycline for acne vulgaris. Pediatr Dermatol. 2007;24:246–249. [PubMed] [Google Scholar]
    7. Smith K, Leyden JJ. Safety of doxycycline and minocycline: a systematic review. Clin Ther. 2005;27:1329–1342. [PubMed] [Google Scholar]
    8. Healy J, Alexander B, Eapen C, Roberts-Thomson IC. Minocycline-induced autoimmune hepatitis. Intern Med J. 2009;39:487–488. [PubMed] [Google Scholar]
    9. Lee SH, Yoon J, Kim TH, Um SH, Yoon TJ. Systemic lupus erythematosus induced by tetracycline. Int J Dermatol. 2013;52:257–258. [PubMed] [Google Scholar]
    10. Elkayam O, Yaron M, Caspi D. Minocycline-induced autoimmune syndromes: an overview. Semin Arthritis Rheum. 1999;28:392–397. [PubMed] [Google Scholar]
    11. Selimoglu MA, Ertekin V. Autoimmune hepatitis triggered by Brucella infection or doxycycline or both. Int J Clin Pract. 2003;57:639–641. [PubMed] [Google Scholar]
    12. Doerge DR, Divi RL, Deck J, Taurog A. Mechanism for the anti-thyroid action of minocycline. Chem Res Toxicol. 1997;10:49–58. [PubMed] [Google Scholar]
    13. Taurog A, Dorris ML, Doerge DR. Minocycline and the thyroid: antithyroid effects of the drug, and the role of thyroid peroxidase in minocycline-induced black pigmentation of the gland. Thyroid. 1996;6:211–219. [PubMed] [Google Scholar]
    14. Hecht DA, Wenig BM, Sessions RB. Black thyroid: A collaborative series. Otolaryngol Head Neck Surg. 1999;121:293–296. [PubMed] [Google Scholar]
    15. Ohaki Y, Misugi K, Hasegawa H. "Black thyroid" associated with minocycline therapy. A report of an autopsy case and review of the literature. Acta Pathol Jpn. 1986;36:1367–1375. [PubMed] [Google Scholar]
    16. Oertel YC, Oertel JE, Dalal K, Mendoza MG, Fadeyi EA. Black thyroid revisited: cytologic diagnosis in fine-needle aspirates is unlikely. Diagn Cytopathol. 2006;34:106–111. [PubMed] [Google Scholar]
    17. Saul SH, Dekker A, Lee RE, Breitfeld V. The black thyroid. Its relation to minocycline use in man. Arch Pathol Lab Med. 1983;107:173–177. [PubMed] [Google Scholar]
    18. Raghavan R, Snyder WH, Sharma S. Pathologic quiz case: tumor in pigmented thyroid gland in a young man. Papillary thyroid carcinoma in a minocycline-induced, diffusely pigmented thyroid gland. Arch Pathol Lab Med. 2004;128:355–356. [PubMed] [Google Scholar]
    19. Pantanowitz L, Tahan SR. Black thyroid. Ear Nose Throat J. 2003;82:676–677. [PubMed] [Google Scholar]
    20. Pantanowitz L. Black thyroid. Diagn Cytopathol. 2007;35:135–136. [PubMed] [Google Scholar]
    21. Doxycycline Information from Drugs.com. Drugscom [Google Scholar]
    22. Minocycline Information from Drugs.com. Drugscom [Google Scholar]
     

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  2. Collden

    Collden Member

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    Well I'll be damned, I was on oral Tetracycline against acne in my teens and if I look at photos from that period it was shortly afterwards that the outer third of my eyebrows started to thin out. At 15 I had rock solid eyebrows and at 17 they were already showing the sign of Hertoghe.

    Then again my siblings are hypothyroid too without having taken this, so might be unrelated.
     
  3. OP
    Tristan Loscha

    Tristan Loscha Member

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    yes,me too,oral tetracycline and minocycline,i want to test labs in regard to this.
     
  4. sun-maid

    sun-maid Member

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    200mg for 23 months is a lot of mino. I wonder if what would happen if they did not treat them for hyperthyroidism.
     
  5. Collden

    Collden Member

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    Did you ever try thyroid hormone replacement therapy? I always figured my hypothyroidism was caused by dieting and exercising for several years, but even doing lots of refeeding and resting for many years did not fully resolve it, would make sense if the thyroid had actually been chemically damaged beforehand.
     
  6. OP
    Tristan Loscha

    Tristan Loscha Member

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    I want to try it,could be a yuge piece of the healthpuzzle,did not run labs for a longer time.
     
  7. raysputin

    raysputin Member

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    I wonder how one could reverse the damage? I’ve had some benefit from taking ancestral supplements thyroid but still have myxedema all over my arms and legs and other issues.
     
  8. Collden

    Collden Member

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    I don't understand the connection between "marked release of thyroid hormone" and the subsequent persistent hypothyroidism, but it seems in this case the drug doesn't cause autoimmune hypothyroidism but simply partially destroys the gland.

    Has Peat commented on whether the thyroid gland can regenerate? Not sure that's possible. If the hypothyroidism is genuinely caused by damage to the gland then it seems you'd need permanent hormone supplementation to treat it.
     
  9. LeeLemonoil

    LeeLemonoil Member

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  10. Collden

    Collden Member

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    From the other thread
    Jesus, this describes me to a T. At 15 I was a normal, healthy-looking teen, although with bad acne. I took tetracycline pills twice a day for 6 months, and from 15 to 17 I gained 35 pounds. Bizarrely all the fat went on my ass and hips, and my face started looking really weird. Up till now I just chalked it up to a very bad puberty, and when a year later I developed strong signs of hypothyroidism including eyebrows falling off I thought it was simply due to dieting and exercising I did to try and get the weight off, but this antibiotic connection is starting to seem more plausible.
     
  11. LeeLemonoil

    LeeLemonoil Member

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    It might be in part due to hormonal mechanisms that are part of puberty. Acne is caused by prolactin, estrogen excess or by cortisol Messing with androgens - and might be aggravated by suppressing thyroid function / homeostasis through mino even further.

    Have you taken retinoid acid - medication also?
     
  12. OP
    Tristan Loscha

    Tristan Loscha Member

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    I would go ancestral on the salt intake and consume no more than 500mg to 1500mg of Sodium =)))
     
  13. OP
    Tristan Loscha

    Tristan Loscha Member

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    1. Treatment Options
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    4. Side Effects
    Print Share
    Minocycline Side Effects
    Medically reviewed by Drugs.com. Last updated on Aug 13, 2019.

    In Summary
    Commonly reported side effects of minocycline include: headache. Other side effects include: vulvovaginal candidiasis, diarrhea, dizziness, dysphagia, epigastric discomfort, melanoglossia, nausea and vomiting, sore throat, stomatitis, and anorexia. See below for a comprehensive list of adverse effects.

    For the Consumer
    Applies to minocycline: oral capsule, oral capsule extended release, oral tablet, oral tablet extended release

    Other dosage forms:

    Side effects requiring immediate medical attention
    Along with its needed effects, minocycline may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

    Check with your doctor immediately if any of the following side effects occur while taking minocycline:

    Incidence not known

    • Black, tarry stools
    • blistering, peeling, or loosening of the skin
    • blood in the urine or stools
    • blurred or double vision
    • bulging soft spot on the head of an infant
    • chest pain, possibly moving to the left arm, neck, or shoulder
    • confusion
    • diarrhea
    • dizziness or lightheadedness
    • eye pain
    • fast heartbeat
    • general feeling of discomfort or illness
    • general tiredness and weakness
    • hives, itching, or skin rash
    • joint or muscle pain
    • large, hive-like swelling on the face, eyelids, lips, tongue, throat, hands, legs, feet, or sex organs
    • loss of appetite
    • nausea or vomiting
    • red skin lesions, often with a purple center
    • severe headache
    • severe stomach pain
    • sores, ulcers, or white spots on the lips or in the mouth
    • troubled breathing
    • unusual bleeding or bruising
    • upper right abdominal or stomach pain
    • yellow eyes and skin
    Side effects not requiring immediate medical attention
    Some side effects of minocycline may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects.

    Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

    Less common

    • Continuing ringing or buzzing or other unexplained noise in the ears
    • difficulty with moving
    • hearing loss
    • hives or welts
    • muscle stiffness
    • redness of the skin
    • sleepiness or unusual drowsiness
    Incidence not known

    • Bloating
    • discoloration of the tooth
    • increased sensitivity of the skin to sunlight
    • indigestion
    • severe sunburn


    For Healthcare Professionals
    Applies to minocycline: intravenous powder for injection, oral capsule, oral capsule extended release, oral suspension, oral tablet, oral tablet extended release, oral and topical kit

    Nervous system
    Very common (10% or more): Headache (up to 23%)

    Common (1% to 10%): Dizziness (lightheadedness), somnolence, tinnitus, vertigo

    Rare (0.01% to 0.1%): Hypoesthesia, paresthesia, intracranial hypertension, impaired/decreased hearing

    Very rare (less than 0.01%): Bulging fontanels (in infants)

    Frequency not reported: Convulsions, sedation, ataxia, benign intracranial hypertension (pseudotumor cerebri), vestibular reactions[Ref]

    Headache, dizziness, vertigo. and ataxia have been reported. These side effects were reversible within 3 to 48 hours of stopping therapy and occurred less often with low doses.

    Pseudotumor cerebri, bulging fontanels (infants), and decreased hearing have also been reported during postmarketing experience.[Ref]

    Dermatologic
    Hyperpigmentation of various body sites (including the skin, nails, teeth, oral mucosa, bones, thyroid, eyes [including sclera, conjunctiva], breast milk, lacrimal secretions, perspiration) has been reported. This blue/black/grey or muddy-brown discoloration was localized or diffuse. The most common site was the skin. Pigmentation often reversed when the drug was discontinued; however, resolution took several months or persisted in some cases. The generalized muddy-brown skin pigmentation sometimes persisted, especially in areas exposed to sun.

    Biopsies of pigmented tissue have shown granules within the cells which stained positive for iron. This pigmentation faded over time after drug discontinuation.

    DRESS syndrome (including fatal cases) has been reported. DRESS syndrome with persistent myocarditis has been reported in at least 3 cases.

    Fixed drug eruptions, erythema multiforme, Stevens-Johnson syndrome, and photosensitivity have also been reported during postmarketing experience.[Ref]

    Common (1% to 10%): Pruritus, urticaria

    Rare (0.01% to 0.1%): Alopecia, erythema multiforme, erythema nodosum, fixed drug eruptions, hyperpigmentation (brownish or bluish-black pigmentation) of skin, photosensitivity, rash, vasculitis

    Very rare (less than 0.01%): Angioedema, exfoliative dermatitis, hyperpigmentation of nails/nail beds, Stevens-Johnson syndrome, toxic epidermal necrolysis

    Frequency not reported: Hyperpigmentation of various body sites (including bones, mucous membranes, teeth, oral mucosa, tongue, thyroid, eyes [including sclera, conjunctiva], breast milk, lacrimal secretions, structures of inner organs), maculopapular rash, erythematous rash, discolored perspiration, Sweet's syndrome (acute febrile neutrophilic dermatosis)

    Postmarketing reports: Anaphylactoid purpura, pigmentation of skin and mucous membranes, angioneurotic edema, drug rash with eosinophilia and systemic symptoms (DRESS)[Ref]

    Gastrointestinal
    Common (1% to 10%): Dry mouth

    Rare (0.01% to 0.1%): Diarrhea, nausea, stomatitis, discoloration of teeth, vomiting

    Very rare (less than 0.01%): Oral and anogenital candidiasis, dyspepsia, dysphagia, enamel hypoplasia, enterocolitis, esophagitis, esophageal ulcerations, glossitis, pancreatitis, pseudomembranous colitis

    Frequency not reported: Antibiotic-associated colitis, oral cavity discoloration (including buccal mucosa, tongue, lip, gum), abdominal cramping, inflammatory lesions (with monilial overgrowth) in the oral and anogenital regions[Ref]

    Pancreatitis has rarely been associated with use of this drug. In 2 case reports, cystic fibrosis patients experienced pancreatitis during treatment with this drug for acute bacterial exacerbations of respiratory disease. The authors suggested that cystic fibrosis patients, as a result of the disease process, may be more susceptible to drug-induced pancreatitis. Additionally, in at least 1 case, multiple concomitant medications were taken; therefore, a temporal relationship between this drug and pancreatitis could not be proven conclusively.

    Esophagitis and esophageal ulcerations have been reported in patients taking the capsule or tablet formulations of tetracycline-class antibiotics. Most of these patients took the drug immediately before going to bed.

    Enterocolitis, pancreatitis, glossitis, dysphagia, and tooth discoloration have also been reported during postmarketing experience.[Ref]

    Musculoskeletal
    Lupus-like reactions induced by this drug have commonly presented with arthralgia or arthritis, myalgia or malaise, and positive ANA titer. Patients with highly positive anti-double stranded DNA (anti-dsDNA) antibodies have rarely been reported. All patients recovered after the drug was discontinued; however, several required short courses of corticosteroids.

    Severe acute myopathy associated with this drug (100 mg orally per day) occurred in a 17-year-old male after strenuous exercise. His laboratory values were as follows: ESR 33 mm/hr, CRP 0.84 mg/dL, creatine kinase 87,297 units/L, AST 1307 units/L, ALT 311 units/L, LDH 4935 units/L, aldolase 12.6 units/L, alkaline phosphatase 145 units/L, GGT 66 units/L. Muscle enzyme levels normalized and his symptoms resolved 1 month after this drug was discontinued.

    IV minocycline plus quinupristin-dalfopristin were associated with myalgia and arthralgia in 36% of neutropenic cancer patients (n=56).[Ref]

    Common (1% to 10%): Arthralgia, myalgia

    Rare (0.01% to 0.1%): Lupus-like syndrome (consisting of positive antinuclear antibody [ANA], arthralgia, arthritis, joint stiffness/swelling, and at least 1 of the following: fever, myalgia, hepatitis, rash, vasculitis)

    Very rare (less than 0.01%): Arthritis, bone discoloration, systemic lupus erythematosus (SLE), exacerbation of SLE, joint stiffness, joint swelling, joint discoloration, myopathy, hypersensitivity-associated rhabdomyolysis

    Postmarketing reports: Polyarthralgia, exacerbation of systemic lupus, transient lupus-like syndrome[Ref]

    Other
    Common (1% to 10%): Fatigue, malaise

    Uncommon (0.1% to 1%): Fever

    Very rare (less than 0.01%): Discoloration of secretions

    Injection:

    -Frequency not reported: Magnesium intoxication (including flushing, sweating, hypotension, depressed reflexes, flaccid paralysis, hypothermia, circulatory collapse, cardiac and CNS depression, respiratory paralysis)[Ref]

    Psychiatric
    Common (1% to 10%): Mood alteration

    Hypersensitivity
    Death has been reported in some cases involving hypersensitivity syndrome, serum sickness-like syndrome, and lupus-like syndrome.

    Pulmonary infiltrates, night sweats, fever, and eosinophilia have developed in several patients receiving this drug. These effects were thought to be due to drug hypersensitivity.

    Case reports have described a severe CNS -pulmonary hypersensitivity syndrome requiring high-dose corticosteroid therapy. Signs and symptoms have included dry cough, fever, ataxia, muscle weakness, numbness, visual abnormalities, abnormal brain MRI, seizures, pulmonary infiltrates, elevated serum IgE, elevated erythrocyte sedimentation rate (ESR), and eosinophilia.

    Eosinophilic pneumonia with relapsing acute respiratory failure requiring mechanical ventilation and corticosteroids has been reported in a 54-year-old woman. Initial symptoms included dry cough, low-grade fever, fatigue, and dyspnea. Eosinophilia, elevated leukocytes, and C-reactive protein (CRP) were noted. At 14 days after being discharged and resuming this drug, the patient developed rapidly progressive respiratory failure again requiring mechanical ventilation.

    Late-onset drug fever (associated with fever, sore throat, abdominal pain, weakness, loose bloody stools, fatigue, 40-pound weight loss, ESR 99 mm/hr, CRP 5 mg/dL, and mild increases in liver enzymes) has been reported in a 15-year-old boy after using this drug for 24 months for acne. After 1 year of therapy, at least 1 other case of late-onset drug fever occurred. Other reported cases of drug fever generally occurred after 2 to 4 weeks of drug exposure.[Ref]

    Rare (0.01% to 0.1%): Anaphylaxis/anaphylactoid reaction (including shock, fatalities)

    Frequency not reported: Hypersensitivity, hypersensitivity syndrome (consisting of cutaneous reaction [e.g., rash, exfoliative dermatitis], eosinophilia, and at least 1 of the following: hepatitis, pneumonitis, nephritis, myocarditis, pericarditis; with or without fever, lymphadenopathy), serum sickness-like syndrome (consisting of fever, urticaria/rash, arthralgia, arthritis, joint stiffness/swelling, lymphadenopathy; with or without eosinophilia), autoimmune vasculitis, drug fever, eosinophilic pneumonitis, drug hypersensitivity (e.g., pulmonary infiltrates, night sweats, fever, eosinophilia), serum sickness, serum sickness-like reactions, severe central nervous system (CNS)-pulmonary hypersensitivity syndrome

    Postmarketing reports: Hypersensitivity reactions, anaphylaxis[Ref]

    Immunologic
    Frequency not reported: Positive antineutrophil cytoplasmic antibody (ANCA) titers, polyarteritis nodosa, ANCA-positive crescentic glomerulonephritis, ANCA-positive vasculitis, autoimmune hepatitis, necrotizing vasculitis and systemic reactions[Ref]

    Rare cases of necrotizing vasculitis and systemic reactions have been reported, characterized by lymphadenopathy, eosinophilia, increased liver function enzyme levels, and dermatologic involvement. In each case, this drug was discontinued and in some cases, corticosteroid therapy was necessary to assist in the resolution of symptoms.[Ref]

    Hepatic
    Rare (0.01% to 0.1%): Increased liver enzymes, hepatitis, autoimmune hepatitis/hepatotoxicity

    Very rare (less than 0.01%): Hepatic cholestasis, hepatic failure (including fatalities), hyperbilirubinemia, jaundice

    Frequency not reported: Autoimmune hepatitis with lupus-like symptoms, increased liver function test values, acute hepatic failure, liver injury, acute hypersensitivity hepatitis associated with eosinophilia and dermatitis[Ref]

    Some hepatic reactions had an autoimmune basis and occurred after several months of therapy.

    In 1 case, a patient developed rapidly progressing liver failure after using this drug for 4 weeks for acne. The patient had stopped this drug 2 weeks prior to onset of malaise. Liver transplantation was considered, but the patient slowly recovered without significant intervention.

    Other reports of immunologically-mediated progressive liver dysfunction have rarely occurred. In 1 case, a patient received a liver transplant after fulminant hepatic failure which was thought to be related to a 3-year history of daily therapy to treat acne. The dose of this drug ranged from 50 to 200 mg/day. A second patient had been using this drug to treat acne for 1 year just prior to seeking medical attention for an "influenza-like" syndrome. Upon hospitalization, it was determined that the patient was experiencing an autoimmune-mediated hepatitis, most probably related to this drug. Resolution of symptoms occurred in both of these cases after therapy was discontinued and each patient had received appropriate supportive medical care.

    Hepatitis and liver failure have also been reported during postmarketing experience.[Ref]

    Renal
    Rare (0.01% to 0.1%): Increased BUN/serum urea, interstitial nephritis, acute renal failure

    Postmarketing reports: Reversible acute renal failure

    Tetracyclines:

    -Frequency not reported: Aggravation of preexisting renal failure, azotemia/uremia, nephrotoxicity (associated with acute fatty liver), renal tubular damage, Fanconi-like syndrome[Ref]

    Nephrotoxicity associated with acute fatty liver has been reported with high tetracycline doses. High serum levels of tetracyclines have been associated with azotemia, hyperphosphatemia, and acidosis in patients with renal dysfunction.

    Degraded tetracycline may cause renal tubular damage and a Fanconi-like syndrome.[Ref]

    Hematologic
    Rare (0.01% to 0.1%): Eosinophilia, leukopenia, neutropenia, thrombocytopenia

    Very rare (less than 0.01%): Hemolytic anemia, pancytopenia

    Frequency not reported: Agranulocytosis, antineutrophil cytoplasmic antibody (ANCA)-positive vasculitis[Ref]

    Hemolytic anemia, thrombocytopenia, and eosinophilia have also been reported during postmarketing experience.[Ref]

    Respiratory
    Rare (0.01% to 0.1%): Cough, dyspnea, pulmonary infiltration

    Very rare (less than 0.01%): Bronchospasm, exacerbation of asthma, pulmonary eosinophilia

    Frequency not reported: Pneumonitis, hypersensitivity pneumonitis, pulmonary lupus, eosinophilic pneumonia, pleural effusions, relapsing acute respiratory failure

    Postmarketing reports: Pulmonary infiltrates with eosinophilia[Ref]

    Cardiovascular
    Rare (0.01% to 0.1%): Myocarditis, pericarditis[Ref]

    Metabolic
    Rare (0.01% to 0.1%): Anorexia

    Tetracyclines:

    -Frequency not reported: Hyperphosphatemia, acidosis[Ref]

    High serum levels of tetracyclines have been associated with azotemia, hyperphosphatemia, and acidosis in patients with renal dysfunction.[Ref]

    Endocrine
    A condition characterized by dark pigmentation (brown-black microscopic discoloration) of the thyroid gland has been reported; however, there was no clinical or laboratory evidence of thyroid dysfunction (unknown clinical implications).

    Brown-black microscopic thyroid discoloration and abnormal thyroid function have also been reported during postmarketing experience.[Ref]

    Very rare (less than 0.01%): Abnormal thyroid function, brown-black microscopic thyroid discoloration

    Frequency not reported: Discolored breast secretions[Ref]

    Genitourinary
    Very rare (less than 0.01%): Balanitis (due to lesions on the glans penis), vulvovaginitis

    Postmarketing reports: Deleterious effects on spermatogenesis[Ref]

    Balanitis has also been reported during postmarketing experience.[Ref]

    Local
    Frequency not reported: Injection site erythema, injection site pain[Ref]

    Oncologic
    Frequency not reported: Papillary thyroid cancer

    Postmarketing reports: Thyroid cancer

    Ocular
    Cases of grey scleral pigmentation and macular pigmentation have been reported in elderly patients after chronic use of this drug (5 to 12 years).[Ref]

    Frequency not reported: Discoloration of conjunctiva, discoloration of lacrimal secretions, grey scleral pigmentation, macular pigmentation[Ref]

    References
    1. Lewis PA, Kearney PJ "Pseudotumor cerebri induced by minocycline treatment for acne vulgaris." Acta Derm Venereol 77 (1997): 83

    2. Chiu AM, Chuenkongkaew WL, Cornblath WT, Trobe JD, Digre KB, Dotan SA, Musson KH, Eggenberger ER "Minocycline treatment and pseudotumor cerebri syndrome." Am J Ophthalmol 126 (1998): 116-21

    3. Matteson EL, Johnson BW, Maher JD "Arthralgias, myalgias, and autoimmune hepatitis with minocycline therapy." J Rheumatol 25 (1998): 1653-4

    4. Delaney RA, Narayanaswamy TR "Pseudo-tumor cerebri and acne." Mil Med 155 (1990): 511

    5. Joy VA "Minocycline and ototoxicity." N Engl J Med 301 (1979): 1450

    6. Friedlander IR "Minocycline and ototoxicity." N Engl J Med 1301 (1979): 1450-1

    7. Weese-Mayer DE, Yang RJ, Mayer JR, Zaparackas Z "Minocycline and Pseudotumor cerebri: The well-known but well-kept secret." Pediatrics 108 (2001): 519-20

    8. Settgast AM, Groth T, Gertner E "Minocycline-induced central nervous system-pulmonary hypersensitivity syndrome." Int J Dermatol 42 (2003): 316-7

    9. Cerner Multum, Inc. "UK Summary of Product Characteristics." O 0

    10. Cerner Multum, Inc. "Australian Product Information." O 0

    11. Donnet A, Dufour H, Graziani N, Grisoli F "Minocycline and benign intracranial hypertension." Biomed Pharmacother 46 (1992): 171-2

    12. "Product Information. Minocin (minocycline)." Lederle Laboratories, Wayne, NJ.

    13. Katz J, Barak S, Shemer J, Langevitz P, Livneh A "Black tongue associated with minocycline therapy." Arch Dermatol 131 (1995): 620

    14. Peyriere H, Dereure O, Breton H, et al. "Variability in the clinical pattern of cutaneous side-effects of drugs with systemic symptoms: does a DRESS syndrome really exist?" Br J Dermatol 155 (2006): 422-8

    15. Huq F, Durso SC "Spurious bruising in a patient taking warfarin: minocycline-induced skin hyperpigmentation." J Am Geriatr Soc 56 (2008): 1156-7

    16. Fleming CJ, Hunt MJ, Salisbury ELC, Mccarthy SW, Barnetson RS "Minocycline-induced hyperpigmentation in leprosy." Br J Dermatol 134 (1996): 784-7

    17. McGrae JD, Zelickson AS "Skin pigmentation secondary to minocycline therapy." Arch Dermatol 116 (1980): 1262-5

    18. Bridges AJ, Graziano FM, Calhoun W, Reizner GT "Hyperpigmentation, neutrophilic alveolitis, and erythema nodosum resulting from minocycline." J Am Acad Dermatol 22 (1990): 959-62

    19. Gordon G, Sparano BM, Iatropoulos MJ "Hyperpigmentation of the skin associated with minocycline therapy." Arch Dermatol 121 (1985): 618-23

    20. MarzoOrtega H, Misbah S, Emery P "Minocycline induced autoimmune disease in rheumatoid arthritis: A missed diagnosis?." Journal of Rheumatology 28 (2001): 377-8

    21. Thibault MJ, Billick RC, Srolovitz H "Minocycline-induced Sweet's syndrome." J Am Acad Dermatol 27 (1992): 801-4

    22. Meyerson MA, Cohen PR, Hymes SR "Lingual hyperpigmentation associated with minocycline therapy." Oral Surg Oral Med Oral Pathol 79 (1995): 180-4

    23. Wolfe ID, Reichmister J "Minocycline hyperpigmentation: skin, tooth, nail, and bone involvement." Cutis 33 (1984): 457-8

    24. Mensing H, Kowalzick L "Acute febrile neutrophilic dermatosis (Sweet's syndrome) caused by minocycline." Dermatologica 182 (1991): 43-6

    25. Odell EW, Hodgson RP, Haskell R "Oral presentation of minocycline-induced black bone disease." Oral Surg Oral Med Oral Pathol 79 (1995): 459-61

    26. Khan Durani B, Jappe U "Drug-induced Sweet's syndrome in acne caused by different tetracyclines: case report and review of the literature." Br J Dermatol 147 (2002): 558-62

    27. Tsao H, Busam K, Barnhill RL, Dover JS "Treatment of minocycline-induced hyperpigmentation with the q-switched ruby laser." Arch Dermatol 132 (1996): 1250-1

    28. Ho NC, McInerney A, Levy H, Francomano CA, Elkayam O "Minocycline-induced generalized postinflammatory elastolysis." Am J Med 109 (2000): 340-1

    29. Tavares J, Leung WW "Discoloration of nail beds and skin from minocycline." CMAJ 183 (2011): 224

    30. Caro I "Discoloration of the teeth related to minocycline therapy for acne." J Am Acad Dermatol 3 (1980): 317-8

    31. Elkayam O, Levartovsky D, Brautbar C, Yaron M, Burke M, Vardinon N, Caspi D "Clinical and immunological study of 7 patients with minocycline-induced autoimmune phenomena." Am J Med 105 (1998): 484-7

    32. Schaffer J, Davidson DM, McNiff JM, Bolognia JL "Perinuclear antineutrophilic cytoplasmic antibody-positive cutaneous polyarteritis nodosa associated with minocycline therapy for acne vulgaris." J Am Acad Dermatol 44 (2001): 198-206

    33. Hung PH, Caldwell JB, James WD "Minocycline-induced hyperpigmentation." J Fam Pract 41 (1995): 183-5

    34. Yamamoto T, Minatohara K "Minocycline-induced acute generalized exanthematous pustulosis in a patient with generalized pustular psoriasis showing elevated level of sELAM-1." Acta Derm Venereol 77 (1997): 168-9

    35. Wetter DA "Minocycline hyperpigmentation." Mayo Clin Proc 87 (2012): e33

    36. Kalai C, Brand R, Yu L "Minocycline-induced Sweet syndrome (acute febrile neutrophilic dermatosis)." J Am Acad Dermatol 67 (2012): e289-91

    37. Tanzi EL, Hecker MS "Minocycline-induced hyperpigmentation of the tongue." Arch Dermatol 136 (2000): 427-8

    38. Boyle MP "Minocycline-induced pancreatitis in cystic fibrosis." Chest 119 (2001): 1283-5

    39. Raad I, Hachem R, Hanna H, et al. "Treatment of vancomycin-resistant enterococcal infections in the immunocompromised host: quinupristin-dalfopristin in combination with minocycline." Antimicrob Agents Chemother 45 (2001): 3202-4

    40. Knights SE, Leandro MJ, Khamashta MA, Hughes GRV "Minocycline-induced arthritis." Clin Exp Rheumatol 16 (1998): 587-90

    41. Matsuura T, Shimizu Y, Fujimoto H, Miyazaki T, Kano S "Minocycline-related lupus." Lancet 340 (1992): 1553

    42. "Minocycline hypersensitivity syndrome manifesting with rhabdomyolysis." Int J Dermatol 41 (2002): 530-531

    43. Narvaez J, Vilaseca-Momplet J "Severe acute myopathy induced by minocycline." Am J Med 116 (2004): 282-3

    44. Gorard DA "Late-onset drug fever associated with minocycline." Postgrad Med J 66 (1990): 404-5

    45. Quilty B, Mchugh N "Lupus-like syndrome associated with the use of minocycline." Br J Rheumatol 33 (1994): 1197-8

    46. Hess EV "Minocycline and autoimmunity." Clin Exp Rheumatol 16 (1998): 519-21

    47. Hara H, Fujitsuka A, Morishima C, Kurihara N, Yamaguchi ZI, Morishima T "Severe drug-induced pneumonitis associated with minocycline and nicotinamide therapy of a bullous pemphigoid." Acta Derm Venereol 78 (1998): 393-4

    48. Akin E, Miller LC, Tucker LB "Minocycline-induced lupus in adolescents." Pediatrics 101 (1998): 926-8

    49. Puyana J, Urena V, Quirce S, Fernandez-Rivas M, Cuevas M, Fraj J "Serum sickness-like syndrome associated with minocycline therapy." Allergy 45 (1990): 313-5

    50. Kounis GN, Kouni SA, Chiladakis JA, Kounis NG "Comment: Mesalamine-Associated Hypersensitivity Myocarditis in Ulcerative Colitis and the Kounis Syndrome (February)." Ann Pharmacother 43 (2009): 393-4

    51. Christodoulou CS, Emmanuel P, Ray RA, Good RA, Schnapf BM, Cawkwell GD "Respiratory distress due to minocycline-induced pulmonary lupus." Chest 115 (1999): 1471-3

    52. Grim SA, Romanelli F, Jennings PR, Ofotokun I "Late-onset drug fever associated with minocycline: case report and review of the literature." Pharmacotherapy 23 (2003): 1659-62

    53. Kaufmann D, Pichler W, Beer JH "Severe episode of high fever with rash, lymphadenopathy, neutropenia, and eosinophilia after minocycline therapy for acne." Arch Intern Med 154 (1994): 1983-4

    54. Ferner RE, Moss C "Minocycline for acne - first line antibacterial treatment of acne should be with tetracycline or oxytetracycline." BMJ 312 (1996): 138

    55. Dykhuizen RS, Zaidi AM, Godden DJ, Jegarajah S, Legge JS "Lesson of the week: minocycline and pulmonary eosinophilia." BMJ 310 (1995): 1520-1

    56. LePaw MI "Fixed drug eruption due to minocycline-report of one case." J Am Acad Dermatol 8 (1983): 263-4

    57. Otero M, Goodpasture HC "Pulmonary infiltrates and eosinophilia from minocycline." JAMA 250 (1983): 2602

    58. Angulo JM, Sigal LH, Espinoza LR "Coexistent minocycline-induced systemic lupus erythematosus and autoimmune hepatitis." Semin Arthritis Rheum 28 (1998): 187-92

    59. Chatham WW, Ross DW "Leukemoid blood reaction to tetracycline." South Med J 76 (1983): 1195-6

    60. Bentur L, Bar-Kana Y, Livni E, et al. "Severe minocycline-induced eosinophilic pneumonia: extrapulmonary manifesations and the use of in vitro immunoassays." Ann Pharmacother 31 (1997): 733-5

    61. Guillon JN, Joly P, Autran B, et al "Minocycline-induced cell-mediated hypersensitivity pneumonitis." Ann Intern Med 117 (1992): 476-81

    62. Gordon PM, White MI, Herriot R, Martin JC, Reid DM "Minocycline-associated lupus erythematosus." Br J Dermatol 132 (1995): 120-1

    63. Shaughnessy KK, Bouchard SM, Mohr MR, Herre JM, Salkey KS "Minocycline-induced drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome with persistent myocarditis." J Am Acad Dermatol 62 (2009): 315-8

    64. Teitelbaum JE, PerezAtayde AR, Cohen M, Bousvaros A, Jonas MM "Minocycline-related autoimmune hepatitis: Case series and literature review." Arch Pediatr Adolesc Med 152 (1998): 1132-6

    65. "Drugs for rheumatoid arthritis." Treat Guidel Med Lett 7 (2009): 37-46

    66. Pohle T, Menzel J, Domschke W "Minocycline and fulminant hepatic failure necessitating liver transplantation." Am J Gastroenterol 95 (2000): 560-1

    67. Angulo JM, Sigal LH, Espinoza LR "Minocycline induced lupus and autoimmune hepatitis." J Rheumatol 26 (1999): 1420-1

    68. Sturkenboom MCJM, Meier CR, Jick H, Stricker BHC "Minocycline and lupuslike syndrome in acne patients." Arch Intern Med 159 (1999): 493-7

    69. Schrodt BJ, Callen JP "Polyarteritis nodosa attributable to minocycline treatment for acne vulgaris." Pediatrics 103 (1999): 503-5

    70. Kettaneh A, Fain O, Ziol M, Lejeune F, EclacheSaudreau V, Biaggi A, GuettierBouttier C, Thomas M "Minocycline-induced systemic adverse reaction with liver and bone marrow granulomas and Sezary-like cells." Am J Med 108 (2000): 353-4

    71. Malakar S, Dhar S, Malakar RS "Is serum sickness an uncommon adverse effect of minocycline treatment?." Arch Dermatol 137 (2001): 100-1

    72. Rosin MA "Viral-like syndrome associated with minocycline." Arch Dermatol 120 (1984): 575

    73. Macneil M, Haase DA, Tremaine R, Marrie TJ "Fever, lymphadenopathy, eosinophilia, lymphocytosis, hepatitis, and dermatitis: a severe adverse reaction to minocycline." J Am Acad Dermatol 36 (1997): 347-50

    74. Dykhuizen RS, Legge JS "Minocycline induced pulmonary eosinophilia." Respir Med 89 (1995): 61-2

    75. Shoji A, Someda Y, Hamada T "Stevens-Johnson syndrome due to minocycline therapy." Arch Dermatol 123 (1987): 18-20

    76. Parneixspake A, Bastujigarin S, Lobut JB, Erner J, Guyetrousset P, Revuz J, Roujeau JC "Minocycline as possible cause of severe and protracted hypersensitivity drug reaction." Arch Dermatol 131 (1995): 490-1

    77. Bhat G, Jordan J, Sokalski S, Bajaj V, Marshall R, Berkelhammer C "Minocycline-induced hepatitis with autoimmune features and neutropenia." J Clin Gastroenterol 27 (1998): 74-5

    78. Shapiro LE, Knowles SR, Shear NH "Comparative safety of tetracycline, minocycline, and doxycycline." Arch Dermatol 133 (1997): 1224-30

    79. Piperno D, Donne C, Loire R, Cordier JF "Bronchiolitis obliterans organizing pneumonia associated with minocycline therapy: a possible cause." Eur Respir J 8 (1995): 1018-20

    80. Sitbon O, Bidel N, Dussopt C, Azarian R, Braud ML, Lebargy F, Fourme T, Deblay F, Piard F, Camus P "Minocycline pneumonitis and eosinophilia - a report on eight patients." Arch Intern Med 154 (1994): 1633-40

    81. Balestrero S, Ciambellotti A, Parodi A, Rebora A "Minocycline-induced lupus-like syndrome." Int J Dermatol 40 (2001): 474-5

    82. Gough A, Chapman S, Wagstaff K, Emery P, Elias E "Minocycline induced autoimmune hepatitis and systemic lupus erythematosus-like syndrome." BMJ 312 (1996): 169-72

    83. Elkayam O, Yaron M, Caspi D "Minocycline induced arthritis associated with fever, livedo reticularis, and pANCA." Ann Rheum Dis 55 (1996): 769-71

    84. Crosson J, Stillman MT "Minocycline-related lupus erythematosus with associated liver disease." J Am Acad Dermatol 36 (1997): 867-8

    85. Gait RC, Affleck AG, Leach IH, Varma S "Perinuclear antineutrophilic cytoplasmic antibody-positive polyarteritis nodosa secondary to minocycline treatment for acne vulgaris." J Am Acad Dermatol 58(5 Suppl 1) (2008): S123-4

    86. Farver DK "Minocycline-induced lupus." Ann Pharmacother 31 (1997): 1160-3

    87. Byrne PAC, Williams BD, Pritchard MH "Minocycline-related lupus." Br J Rheumatol 33 (1994): 674-6

    88. Sethi S, Sahani M, Oei LS "ANCA-positive crescentic glomerulonephritis associated with minocycline therapy." Am J Kidney Dis 42 (2003): E27-31

    89. Golstein PE, Deviere J, Cremer M "Acute hepatitis and drug-related lupus induced by minocycline treatment." Am J Gastroenterol 92 (1997): 143-6

    90. Margolis DJ, Hoffstad O, Bilker W "Association or lack of association between tetracycline class antibiotics used for acne vulgaris and lupus erythematosus." Br J Dermatol 15 (2007): 540-6

    91. Gordon MM, Porter D "Minocycline induced lupus: Case series in the West of Scotland." J Rheumatol 28 (2001): 1004-6

    92. Masson C, Chevailler A, Pascaretti C, Legrand E, Bregeon C, Audran M "Minocycline related lupus." J Rheumatol 23 (1996): 2160-1

    93. Knowles SR, Shapiro L, Shear NH "Serious adverse reactions induced by minocycline: report of 13 patients and review of the literature." Arch Dermatol 132 (1996): 934-9

    94. Harel L, Amir J, Livni E, Straussberg RS, Varsano I "Serum-sickness-like reaction associated with minocycline therapy in adolescents." Ann Pharmacother 30 (1996): 481-3

    95. Min DI, Burke PA, Lewis D, Jenkins RL "Acute hepatic failure associated with oral minocycline: a case report." Pharmacotherapy 12 (1992): 68-71

    96. Malcolm A, Heap TR, Eckstein RP, Lunzer MR "Minocycline-induced liver injury." Am J Gastroenterol 91 (1996): 1641-3

    97. Nietsch HH, Libman BS, Pansze TW, Eicher JN, Reeves JRT, Krawitt EL "Minocycline-induced hepatitis." Am J Gastroenterol 95 (2000): 2993-5

    98. Burette A, Finet C, Prigogine T, De Roy G, Deltenre M "Acute hepatic injury associated with minocycline." Arch Intern Med 144 (1984): 1491-2

    99. Seaman HE, Lawrenson RA, Williams TJ, MacRae KD, Farmer RDT "The risk of liver damage associated with minocycline: A comparative study." J Clin Pharmacol 41 (2001): 852-60

    100. Oddo M, Liaudet L, Lepori M, Broccard AF, Schaller MD "Relapsing acute respiratory failure induced by minocycline." Chest 123 (2003): 2146-8

    101. Landas SK, Schelper RL, Tio FO, Turner JW, Moore KC, Bennett-Gray J "Black thyroid syndrome: exaggeration of a normal process?" Am J Clin Pathol 85 (1986): 411-8

    102. Ohaki Y, Misugi K, Hasegawa H ""Black thyroid" associated with minocycline therapy." Acta Pathol Jpn 36 (1986): 1367-75

    103. Bradfield YS, Robertson DM, Salomao DR, Link TP, Rostvold JA "Photo essay: minocycline-induced ocular pigmentation." Arch Ophthalmol 121 (2003): 144-5



    Medicina (B Aires). 2017;77(5):394-404.
    Drug-induced hypothyroidism.
    Rizzo LFL1, Mana DL2, Serra HA3.
    Author information
    Abstract

    The thyroid axis is particularly prone to interactions with a wide variety of drugs, whose list increases year by year. Hypothyroidism is the most frequent consequence of drug-induced thyroid dysfunction. The main mechanisms involved in the development of primary hypothyroidism are: inhibition of the synthesis and/or release of thyroid hormones, immune mechanisms related to the use of interferon and other cytokines, and the induction of thyroiditis associated with the use of tyrosine kinase inhibitors and drugs blocking the receptors for vascular endothelial growth factor. Central hypothyroidism may be induced by inhibition of thyroid-stimulating hormone (bexarotene or corticosteroids) or by immunological mechanisms (anti-CTLA4 or anti-PD-1 antibody drugs). It is also important to recognize those drugs that generate hypothyroidism by interaction in its treatment, either by reducing the absorption or by altering the transport and metabolism of levothyroxine. Thus, it is strongly recommended to evaluate thyroid function prior to the prescription of medications such as amiodarone, lithium, or interferon, and the new biological therapies that show important interaction with thyroid and endocrine function in general.

    KEYWORDS:
    drugs; hypothyroidism; thyroid

    PMID:
    29044016





    Horm Res Paediatr. 2019;92(4):276-283. doi: 10.1159/000502843. Epub 2019 Sep 18.
    Case Series: Minocycline-Associated Thyroiditis.
    Millington K1, Charrow A2, Smith J3.
    Author information
    Abstract

    INTRODUCTION:
    Minocycline, a member of the tetracycline class of antibiotics, has been associated with benign thyroid pigmentation but reports of thyroid dysfunction are sparse.

    METHODS:
    Cases were selected via an inquiry of the electronic medical records for patients with thyroid dysfunction and the use of a tetracycline antibiotic. Non-autoimmune thyroiditis was defined as abnormally low or suppressed thyroid-stimulating hormone (TSH, <0.3 µIU/mL), elevated free thyroxine or total thyroxine, and undetectable antithyroid antibodies.

    RESULTS:
    Nine cases of thyroiditis without autoimmunity were identified out of 423 reviewed patients. Cases of thyroiditis occurred in adolescents ages 14-17 years who had been taking minocycline for 6 months to 4 years. In all cases, minocycline was prescribed for the treatment of acne. Four of the 9 received treatment for thyrotoxicosis with a β-blocker (in 3 cases) and/or antithyroid drug (in 2 cases). Thyroiditis was symptomatic in all but one individual who presented with painless goiter. All thyroiditis was transient and resolved after a median of 4.5 months (range 2-5 months). In one case, thyroiditis was followed by transient hypothyroidism.

    DISCUSSION:
    Minocycline is known to cause thyroid abnormalities, although it has not been definitively linked to thyroid dysfunction. Here, we report 9 cases of non-autoimmune thyroiditis in adolescents receiving minocycline for acne. We recommend that minocycline exposure be considered in the differential diagnosis for thyroiditis and that patients receiving minocycline be counseled regarding the risk of thyroid dysfunction.

    © 2019 S. Karger AG, Basel.

    KEYWORDS:
    Acne; Minocycline; Tetracycline; Thyroiditis

    PMID:
    31533103
    PMCID:
    PMC7078063
    [Available on 2020-09-18]
    DOI:
    10.1159/000502843
     
  14. OP
    Tristan Loscha

    Tristan Loscha Member

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    Hormone Research in Paediatrics
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    Novel Insights from Clinical Practice / Case Report
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    Case Series: Minocycline-Associated Thyroiditis
    Millington K.a · Charrow A.b · Smith J.a
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    Corresponding Author

    Keywords: ThyroiditisMinocyclineTetracyclineAcne


    Horm Res Paediatr 2019;92:276–283
    https://doi.org/10.1159/000502843
    Abstract
    Introduction: Minocycline, a member of the tetracycline class of antibiotics, has been associated with benign thyroid pigmentation but reports of thyroid dysfunction are sparse. Methods: Cases were selected via an inquiry of the electronic medical records for patients with thyroid dysfunction and the use of a tetracycline antibiotic. Non-autoimmune thyroiditis was defined as abnormally low or suppressed thyroid-stimulating hormone (TSH, <0.3 µIU/mL), elevated free thyroxine or total thyroxine, and undetectable antithyroid antibodies. Results: Nine cases of thyroiditis without autoimmunity were identified out of 423 reviewed patients. Cases of thyroiditis occurred in adolescents ages 14–17 years who had been taking minocycline for 6 months to 4 years. In all cases, minocycline was prescribed for the treatment of acne. Four of the 9 received treatment for thyrotoxicosis with a β-blocker (in 3 cases) and/or antithyroid drug (in 2 cases). Thyroiditis was symptomatic in all but one individual who presented with painless goiter. All thyroiditis was transient and resolved after a median of 4.5 months (range 2–5 months). In one case, thyroiditis was followed by transient hypothyroidism. Discussion: Minocycline is known to cause thyroid abnormalities, although it has not been definitively linked to thyroid dysfunction. Here, we report 9 cases of non-autoimmune thyroiditis in adolescents receiving minocycline for acne. We recommend that minocycline exposure be considered in the differential diagnosis for thyroiditis and that patients receiving minocycline be counseled regarding the risk of thyroid dysfunction.

    © 2019 S. Karger AG, Basel

    Established Facts
    • Several medications are known to cause non-autoimmune thyroiditis.

    • Minocycline causes thyroid pigmentation “black thyroid” which is thought to be a benign occurrence.
    Novel Insights
    • Minocycline is associated with non-autoimmune thyroiditis.

    • Clinicians prescribing minocycline should monitor patients for symptoms of thyroid dysfunction.
    Introduction
    Minocycline, a tetracycline antibiotic, is commonly prescribed for acne vulgaris (acne) in adolescents and adults. Minocycline has several well-documented adverse effects including an association with autoimmunity, in particular autoimmune hepatitis, drug-induced lupus, and vasculitis [1]. With long-term use, it also has a propensity to deposit pigment (both iron and hemosiderin) throughout the bone, skin, and soft tissue [2]. Pigmentation of the thyroid gland, i.e., “black thyroid,” has been noted on autopsy and postoperative pathology in patients receiving minocycline [2-4]. The early reports of black thyroid did not describe any disturbance in thyroid function [3, 5-7]; however, 2 later cases reported an association with hypothyroidism [8]. There have been reports of thyroiditis associated with minocycline treatment in adults, although these were in association with severe autoimmune conditions and/or with evidence of thyroid autoimmunity [9, 10]. There is only one previous report of the development of thyroiditis in patients receiving minocycline in the absence of underlying thyroid autoimmunity [11]. We report an additional 9 cases of minocycline associated non-autoimmune thyroiditis.

    Methods
    The Boston Children’s Hospital Electronic Medical Record was queried using the ICD-9 or ICD-10 code for thyroid disorder and tetracycline antibiotics. Results were limited to those who presented to the outpatient endocrine clinic between 1 January 2000 and 1 July 2018. Patients with thyroid cancer, congenital hypothyroidism, thyroid nodules, trisomy 21, or type 1 diabetes mellitus were excluded. Additionally, patients who were taking medications known to affect thyroid function such as lithium salts, amiodarone, antiseizure drugs, or who had evidence of thyroid autoimmunity as reflected by the presence of thyroperoxidase (TPO) or thyroglobulin (Tg) antibodies, were excluded. Patients were included if they had levels of thyroid-stimulating hormone (TSH), thyroxine (T4), or free thyroxine (free T4) outside of the reference range at any time. Medical record abstraction was performed for subjects to confirm that they met the inclusion criteria, and also to document symptoms, tetracycline antibiotic use, and laboratory findings.

    Results
    Four hundred and twenty-three patients were reviewed, 23 of whom met the inclusion criteria. Of these, 10 had evidence of subclinical hyperthyroidism defined as suppressed TSH <0.3 µIU/mL, normal free T4, and total tri-iodothyronine (T3); 3 had subclinical hypothyroidism (TSH >5.7 µIU/mL, normal free T4, and total T3); and 1 had primary hypothyroidism. Nine patients had thyroiditis, and their cases are summarized here (Table 1).

    [​IMG]
    Case 1
    A 17-year-old male developed tachycardia, palpitations, myalgias, insomnia, and restlessness approximately 11 months after starting oral minocycline 200 mg daily for the treatment of acne. There was no family history of thyroid dysfunction, and the patient was not taking other medications. On examination, the thyroid was normal in size and texture, and without evidence of nodularity. Serum TSH concentration was <0.005 µIU/mL (reference range 0.7–5.7 µIU/mL), Free T4 was elevated at 5.21 ng/dL (reference range 0.8–1.9 ng/dL) and total T3 was elevated at 420 ng/dL (reference range 80–210 ng/dL). Anti-TPO, anti-Tg, and thyrotropin receptor antibodies (TRAbs) were undetectable. Thyrotropin-stimulating immunoglobulins (TSI) were likewise negative. Scintigraphy with I-123 demonstrated low uptake (4% at 4 h and 2% at 24 h) consistent with acute thyroiditis. The patient was treated with β-blockade for symptomatic tachycardia. Upon discontinuation of minocycline, his symptoms resolved in 1 month; restoration of euthyroidism occurred by 3 months.

    Case 2
    A 16-year-old male presented with weight loss, fatigue, palpitations, and diarrhea while receiving oral minocycline 200 mg daily for 4 years for acne. There was no family history of thyroid dysfunction. His thyroid was of normal size, texture, and without evidence of nodularity. TSH was suppressed at <0.005 µIU/mL (reference range 0.358–3.74 µIU/mL) and free T4 was elevated at 2.13 ng/dL (reference range 0.76–1.46 ng/dL). Anti-TPO, anti-Tg, and TRAbs antibodies were undetectable. After minocycline was discontinued, thyrotoxicosis improved in 1 week, with total T4 9.2 μg/dL (reference range 4.7–12.4 μg/dL), TSH-binding ratio (THBR) 1.11 (reference range 0.88–1.08), and T3 132 ng/dL (reference range 80–210 ng/dL). TSH remained suppressed for 2 months, after which time the patient experienced transient subclinical hypothyroidism, TSH 10.43 µIU/mL (reference range 0.27–4.2 µIU/mL) and free T4 0.92 ng/dL (reference range 0.9–1.7 ng/dL). Euthyroidism was restored 5 months after discontinuation of minocycline.

    Case 3
    A 15-year-old female was found to be hypertensive, tremulous, and hyperreflexic during evaluation for mood lability. She had been taking oral minocycline for acne for an unknown duration as well as sertraline for depression and albuterol for asthma. The thyroid was palpated at 1.5 times (20–25 g) the normal size without evidence of a focal nodule. There was a history of hypothyroidism in the patient’s mother. Serum TSH concentration was <0.005 µIU/mL (reference range 0.7–5.7 µIU/mL). T4 and T3 were both elevated at 11.3 μg/dL (reference range 5.2–10.7 μg/dL) and 189 ng/dL (reference range 86–153 ng/dL), respectively. Anti-TPO, anti-Tg, TRAbs, and TSI antibodies were not detectable. Upon discontinuation of the minocycline, the thyrotoxicosis resolved, and euthyroidism was restored by 4 months.

    Case 4
    Approximately 15 months after starting treatment with oral minocycline 100 mg daily for acne, a 16-year-old male experienced palpitations and weight loss. His thyroid was normal in size and texture without appreciable nodules. Upon evaluation, his serum TSH was suppressed to 0.006 µIU/mL (reference range 0.370–5.22 µIU/mL) and free T4 was mildly elevated at 1.91 ng/dL (reference range 0.7–1.9 ng/dL). Anti-TPO, anti-Tg, TRAbs, and TSI were negative. He was treated symptomatically with β-blockade for heart palpitations. The thyrotoxicosis resolved 3 months after the discontinuation of minocycline.

    Case 5
    A 17-year-old female presented with biochemical evidence of thyrotoxicosis during an evaluation for secondary amenorrhea. She had begun treatment with oral minocycline 200 mg daily for acne 1 year earlier. Her thyroid was smooth, not enlarged, and without nodularity. TSH was suppressed to 0.019 µIU/mL (reference range 0.7–5.7 µIU/mL). T4 was elevated at 12.5 µg/dL (reference range 4.7–12.4 µg/dL) with THBR 1.22 (0.77–1.16). Anti-TPO, anti-Tg, TRAbs, and TSI were negative. Thyrotoxicosis resolved within 2 months of discontinuation of minocycline treatment. The patient was started on oral contraceptive medication and experienced regular menses.

    Case 6
    A 17-year-old female presented for evaluation of fatigue, at which time she was found to have a suppressed TSH at 0.006 µIU/mL (reference range 0.7–5.7 µIU/mL) and elevated free T4 of 2.34 ng/dL (reference range 0.80–1.9). On exam, her thyroid was normal in size, texture, and without nodules. The T3 was normal at 194 ng/dL (reference range 80–210 ng/dL). Six months prior, she had started on oral minocycline 100 mg daily for acne. Anti-TPO, anti-Tg, and TRAbs were negative. Thyrotoxicosis resolved 5 months after the discontinuation of minocycline.

    Case 7
    A 15-year-old female presented with weight loss and fatigue 8 months after initiating oral minocycline 100 mg daily for acne. There was a family history of hypothyroidism in the patient’s mother and maternal grandmother. Her thyroid was smooth in texture, not enlarged, and without nodularity. TSH was suppressed at 0.020 µIU/mL (reference range 0.27–4.2 µIU/mL) and T4 was elevated at 15.6 µg/dL (reference range 4.6–12.0 µg/dL). Anti-TPO, anti-Tg, TRAbs, and TSI were negative. Minocycline was discontinued, and antithyroid drug (methimazole) treatment was started at 10 mg 3 times daily. After 5 months, the patient’s symptoms improved, and methimazole was discontinued. The result of follow-up thyroid function testing was within normal limits. Fifteen months later she developed subclinical hypothyroidism, which spontaneously resolved after 2 years.

    Case 8
    A 14-year-old female presented with thyrotoxicosis after evaluation for anxiety, weight loss, and insomnia. Eight months prior, she had begun treatment with oral minocycline for acne. There was no family history of thyroid disease. Her thyroid was smooth, not enlarged, and without palpable nodules. TSH was suppressed 0.013 µIU/mL (reference range 0.7–5.7 µIU/mL). Free T4 and Total T3 were elevated at 4.82 ng/dL (reference range 0.8–1.9 ng/dL) and 223 ng/dL (reference range 80–210 ng/dL), respectively. Anti-TPO, anti-Tg, and TRAbs were negative. The patient was treated with the antithyroid drug methimazole 10 mg twice daily and β-blockade for 1 month. Scintigraphy with I-123 was performed 10 days after the discontinuation of methimazole and demonstrated low uptake (3% at 4 h and 1% at 24 h), consistent with thyroiditis. Her thyrotoxic symptoms improved within 1 month, and the restoration of euthyroidism was documented 5 months later.

    Case 9
    A 16-year-old female presented with biochemical evidence of thyrotoxicosis during an evaluation for possible goiter. She was taking oral minocycline 150 mg daily for acne for an unknown duration. There was no family history of thyroid dysfunction. On examination, her thyroid was smooth, not enlarged, and had no nodules. TSH was suppressed 0.03 µIU/mL (reference range 0.34–5.6 µIU/mL), T4 was elevated at 14.4 µg/dL (reference range 5.0–12.2 µg/dL) and free T4 3.19 ng/dL (reference range 0.54–1.64 ng/dL). Anti-TPO and anti-Tg were negative. Minocycline was discontinued. After 2 months, free T4 had improved to 0.96 ng/dL (reference range 0.8–1.9 ng/dL), although TSH remained <0.01 µIU/mL (reference range 0.7–5.7 µIU/mL) for 5 months.

    Discussion
    We report here 9 cases of thyroiditis in adolescents receiving minocycline for the treatment of acne. Non-autoimmune thyroiditis associated with tetracycline use has been reported, and this is the largest series to date [11].

    Tetracycline antibiotics were discovered in the early 1940s, and the first in the class, aureomycin, was approved by the US Food and Drug Administration (FDA) for clinical use in December 1948. Following the publication of the tetracycline class molecular structure in 1952, synthetic modifications of the core molecule produced compounds with increased stability and efficacy including doxycycline (FDA-approved in 1967), and minocycline (FDA-approved in 1971) [12, 13]. Tetracyclines exert their bacteriostatic effect by binding to a highly conserved site within the 30S ribosomal subunit, interfering with transfer-RNA docking, and thus preventing protein translation [14]. Oral tetracyclines, chiefly doxycycline and minocycline, are routinely used in the treatment of acne for their antibacterial as well as anti-inflammatory properties. Minocycline is the only FDA-approved antibiotic for the treatment of moderate to severe inflammatory acne and is considered the first-line therapy in combination with a topical retinoid [15, 16].

    Minocycline has the greatest lipid solubility of drugs in the tetracycline class, leading to a greater ability to penetrate tissues and a more variable half-life. After prolonged use, the half-life of minocycline can vary from 12 to 23 h, due to the release of drug by bodily lipids [17, 18]. In a study on patients with a minocycline-induced drug rash with eosinophilia and systemic symptoms (DRESS), 6 of the 8 patients had detectable serum levels of minocycline for up to 17 months after cessation of the drug [19].

    Pigmentation of multiple tissues, including the skin, teeth, and bone is a well-known adverse effect of tetracyclines, minocycline in particular [2]. Pigmentation of the thyroid, so-called “black thyroid,” was first reported in humans in 1976 after several reports of this phenomenon in animals [3, 20]. Electron microscopic analysis of the pigment revealed its presence both in colloid and within lysosomal structures in follicular epithelial cells [3, 7]. In animal studies, thyroid pigmentation by minocycline was prevented by coadministration of propylthiouracil or TSH supplements. Both decreased endogenous TSH production and led to the hypothesis that the pigmentation was linked to the synthesis of TSH [20]. This observation was further supported by studies in rats showing that minocycline administration leads to goiter, increased radioactive iodine uptake by the thyroid, and decreased TSH synthesis [21]. Taurog et al. [22] demonstrated that incubation of minocycline with TPO resulted in the oxidation of minocycline and/or its metabolites and the formation of black pigment. In vitro studies with minocycline demonstrated it to be a potent inhibitor of TPO-guided iodination and coupling of mono-iodotyrosine and di-iodotyrosine to form TSH [22, 23]. In addition to the inhibition of TPO by minocycline, other proposed mechanisms of pigment deposition include (1) the binding of minocycline degradation products with lipofuscin, a normally occurring intracytoplasmic pigment associated with aging, (2) the acceleration and accentuation of lipofuscin development, (3) the accumulation of oxidized metabolites of minocycline, and (4) lysosome dysfunction given the presence of pigment in lysosomal-type structures [7, 8, 24, 25].

    “Black thyroid” has been noted in patients after a wide range of tetracycline exposure as well as in those who discontinued the drug. Pigment deposition may occur early in the treatment course and represents a permanent alteration in the thyroid [4, 26]. The relatively common finding of “black thyroid” and the potential for thyroid dysregulation has led many authors to call for the routine monitoring of thyroid function in patients taking tetracyclines.

    Drug-associated thyrotoxicosis has been reported in patients receiving amiodarone, lithium, interferon-α, interleukin-2, tyrosine kinase inhibitors, and checkpoint inhibitor immunotherapy. Mechanisms of drug-associated thyrotoxicosis include delivery of an increased iodine load, as is the case in amiodarone-associated thyroiditis, and the release of preformed TSH through direct destruction of thyroid follicular cells and via the induction of thyroid autoimmunity [25, 27-32].

    To our knowledge, there are 6 cases reported in the literature of thyrotoxicosis associated with minocycline treatment (Table 2). Three of these were reported by Pollock et al. [11] in 2016 in a study of otherwise healthy adolescents receiving minocycline for the treatment of acne. Another case reported by Benjamin and Calikoglu [33] was a 16-year-old male who also received minocycline for acne. This was confounded by the presence of a lupus-like syndrome, arthritis of the ankles, and positive markers of autoimmunity. After discontinuing minocycline, his thyroid dysfunction and arthritis resolved, and the laboratory tests normalized. Tacon et al. [34] reported a case of a 31-year-old female who presented with antibody-negative thyroiditis and a right-sided nodule. Upon fine-needle aspiration, cytology was suspicious for papillary thyroid carcinoma. The patient proceeded to total thyroidectomy, which revealed a “black thyroid” with histologic evidence of drug-induced thyroiditis similar to that observed with amiodarone exposure [34]. Thyroiditis was noted in association with several cases of DRESS associated with minocycline, although systemic symptoms including fever and rash were also observed in these cases [9, 10].

    [​IMG]
    In this case series, we report 9 additional cases of thyroiditis following minocycline treatment for acne. This is the largest reported series to date. Similar to previous cases, these patients developed thyroiditis after a wide range of minocycline exposures. In all cases, thyroiditis resolved 5 months after drug discontinuation, except for 1 in which transient hypothyroidism developed.

    The concentration of minocycline and/or its metabolites in the thyroid have been demonstrated by the observation of “black thyroid” in patients taking minocycline, and the histologic effect on the thyroid appears similar to that induced by amiodarone exposure [34]. Although further studies are needed to completely elucidate the mechanism of minocycline-induced thyroiditis, we propose that minocycline concentrates in the thyroid follicular cells where it and/or its metabolites are oxidized by TPO, leading to cytotoxic damage and the release of preformed TSH. This appears to be a self-limiting process that resolves after discontinuation of the drug. Treatment with antithyroid medications which inhibit TSH formation may not be warranted, and in the 2 reported cases, methimazole failed to hasten the resolution of thyroiditis. Similar to other known mechanisms of drug-induced thyroiditis, minocycline-induced thyroiditis is not dependent on the presence or development of thyroid autoimmunity. Minocycline causes non-autoimmune thyroiditis and may do so more frequently than previously appreciated. Exposure to minocycline should be considered in the differential of a patient presenting with thyroiditis. If discovered, minocycline-associated thyroiditis should be treated similarly to other forms of drug-induced thyroiditis, by discontinuing minocycline, symptomatic management with β-blockade if indicated, and laboratory monitoring of thyroid function.

    Our report is limited by its retrospective nature and single study site. Follow-up information was limited, especially as most patients had a resolution of their symptoms and did not return for further evaluation. Although we noted an association between minocycline use and the development of thyroiditis, we could not establish causality in this observational study. Further prospective studies are needed to determine the incidence of thyroiditis in patients taking minocycline as well as to investigate a potential mechanism.

    Given the propensity of minocycline to cause other autoimmune syndromes, it is possible that it affects thyroid function via an underlying immune mechanism. However, in the absence of other symptoms, it is difficult to isolate the minocycline effect from autoimmune thyroiditis unrelated to drug exposure. Further controlled prospective studies are needed to address the development of autoimmune thyroiditis in patients taking minocycline.

    Nearly all adolescents are affected by some degree of acne, and in up to 20% the acne is moderate or severe [35]. Oral minocycline is the first-line therapy for moderate to severe acne and represents up to half of all oral antibiotics prescribed for this indication [16, 36]. Estimates of adverse events occurring with minocycline use are as high as 72 per million prescriptions, compared to 13 per million prescriptions for doxycycline, another commonly prescribed tetracycline. Many of the adverse events associated with minocycline are mild gastrointestinal and vestibular disturbances; however, there are reports of fatal reactions including DRESS and hepatitis [37, 38]. Minocycline is known to concentrate in the thyroid, leading to “black thyroid,” which was thought to be a benign finding. However, we have observed that minocycline can also lead to non-autoimmune thyroiditis in adolescents at any time during the treatment course. Although there is not enough evidence to recommend the routine monitoring of thyroid function, we do suggest that a history of minocycline exposure be elicited in any patient presenting with thyrotoxicosis while taking minocycline.

    Conclusion
    Long known to cause thyroid pigmentation, it is hypothesized that minocycline can also lead to non-autoimmune thyroiditis. Acne is a common condition in adolescents for which minocycline is utilized. Clinicians prescribing minocycline should be aware of its potential to cause thyroiditis and should counsel patients regarding the symptoms of thyrotoxicosis. Patients presenting with thyroiditis should also be queried about the history of minocycline use. Further studies are needed to determine the cause and frequency of minocycline-induced thyroiditis.

    Statement of Ethics
    The study was approved by the local ethics committee, the Institutional Review Board of Boston Children’s Hospital. As this was a retrospective chart review, written informed consent from subjects was not required.

    Disclosure Statement
    The authors have no conflicts of interest to declare.

    Funding Sources
    K.M. was supported by NIH grant T32-DK007699.

    Author Contributions
    K.M. and J.S. conceptualized and designed the study. K.M. collected and analyzed the data and drafted the initial manuscript with A.C. All authors reviewed and approved the final version of the manuscript
     

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  15. OP
    Tristan Loscha

    Tristan Loscha Member

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    Medicina (B Aires). 2017;77(5):394-404.
    Drug-induced hypothyroidism.
    Rizzo LFL1, Mana DL2, Serra HA3.
    Author information
    1
    Dirección Médica Química Montpellier SA, Argentina.
    2
    Dirección Médica Química Montpellier SA, Argentina. E-mail: daniela.mana@gmail.com.
    3
    Cátedra de Farmacología, Facultad de Ciencias Médicas, U.C.A., Buenos Aires, Argentina.
    Abstract
    The thyroid axis is particularly prone to interactions with a wide variety of drugs, whose list increases year by year. Hypothyroidism is the most frequent consequence of drug-induced thyroid dysfunction. The main mechanisms involved in the development of primary hypothyroidism are: inhibition of the synthesis and/or release of thyroid hormones, immune mechanisms related to the use of interferon and other cytokines, and the induction of thyroiditis associated with the use of tyrosine kinase inhibitors and drugs blocking the receptors for vascular endothelial growth factor. Central hypothyroidism may be induced by inhibition of thyroid-stimulating hormone (bexarotene or corticosteroids) or by immunological mechanisms (anti-CTLA4 or anti-PD-1 antibody drugs). It is also important to recognize those drugs that generate hypothyroidism by interaction in its treatment, either by reducing the absorption or by altering the transport and metabolism of levothyroxine. Thus, it is strongly recommended to evaluate thyroid function prior to the prescription of medications such as amiodarone, lithium, or interferon, and the new biological therapies that show important interaction with thyroid and endocrine function in general.

    KEYWORDS:
    drugs; hypothyroidism; thyroid

    PMID:
    29044016




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  16. Momentum

    Momentum Member

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    I would think iodine would help repair the damage. At the very least it would certainly re-nourish the thyroid gland.
    steppingstonesliving.com has great info on iodine.
     
  17. OP
    Tristan Loscha

    Tristan Loscha Member

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    how does the thyroid gets repaired,would like to re-nourish my glands!,i do not have much hope that it works though?
     
  18. sun-maid

    sun-maid Member

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    Only one got persistent hypothyroidism and it was after taking methimazole and propanolol..
    One guy took 200mg for four year. Thats crazy.
     
  19. methylenewhite

    methylenewhite Member

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    Sweet find. Would get one more mino course probably.
     
  20. cyclops

    cyclops Member

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    But these are like all the antibiotics Peat recommends sometimes..
     
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