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

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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
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The publisher's final edited version of this article is available at J Pediatr
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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
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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
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Collden

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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.
 
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Tristan Loscha
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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.

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

sun-maid

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Sep 19, 2019
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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.
 

Collden

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yes,me too,oral tetracycline and minocycline,i want to test labs in regard to this.
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.
 
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Tristan Loscha
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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.

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

LUH 3417

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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.
 

Collden

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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
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.
 

Collden

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From the other thread
I’ve seen 3 persons that got mino for 6-12 month for acne in low doses daily, 50mg.
All took it in their 15-17 years of age. Severe problems later on, one is a cellular energy wreck. Mitos busted. One seems like estrogenized. I couldn’t never figure that out, maybe crashing thyroid is the explanation. If thyroxine is so heavily affected then t3 too als the study didn’t test that (absurdely)
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 **** 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.
 

LeeLemonoil

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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?
 
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Tristan Loscha
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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.

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

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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
 
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Tristan Loscha
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Hormone Research in Paediatrics
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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).


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].


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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Tristan Loscha
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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: [email protected].
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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Momentum

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Dec 9, 2019
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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.
 
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Tristan Loscha
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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.

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

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

cyclops

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