Tristan Loscha
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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.2–4 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.
Go to:
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.
Go to:
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
Go to:
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 vasculitis8–10; 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.14–16 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).17–20
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.
Go to:
Acknowledgments
Funded by the National Institutes of Health (Postdoctoral Fellowship grant T32 DK077586-06A1).
Go to:
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]
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
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.2–4 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.
Go to:
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.
Go to:
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
Go to:
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 vasculitis8–10; 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.14–16 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).17–20
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.
Go to:
Acknowledgments
Funded by the National Institutes of Health (Postdoctoral Fellowship grant T32 DK077586-06A1).
Go to:
Abbreviations
TSH thyroid stimulating hormone
TPO thyroid perioxidase
TSI thyroid stimulating immunoglobulins
Free T4 free thyroxine
TRAb TSH receptor antibodies
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Footnotes
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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]