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Longevity Library · Lab reference

Written by Daniel Tagge, MD
Updated October 10, 2026
Reviewed October 12, 2026
41 sources · Measured in IU/mL

System: Gut-Immune Health

TPO antibodiesThyroid peroxidase antibodies · Anti-TPO · Thyroid autoantibodies

A positive TPO antibody marks autoimmune thyroiditis, not hypothyroidism: about 11 percent of Americans carry it, most with a normal TSH, and in a 20-year British cohort antibodies alone raised the odds of later hypothyroidism 8-fold in women while antibodies plus a raised TSH raised them 38-fold. Selenium lowers the titer in pooled trials without proven clinical benefit, thyroid hormone did not improve live births in 952 antibody-positive women with normal thyroid function, and the cutoff for 'positive' varies several-fold between laboratory methods.

Thyroid peroxidase is the enzyme that puts iodine into thyroid hormone, and antibodies against it are the most common sign that the immune system has turned on the gland. A positive result is common in well people and does not itself mean the thyroid is failing. The cohorts measure how much it raises the odds of hypothyroidism later; the trials ask whether lowering the titer helps anything, and so far the answer is no. This page gives the numbers, the assay problem, and the situations that belong with a physician.

01 · The scale

Where the laboratory range and the evidence sit.

A positive antibody raised the odds of later hypothyroidism 8-fold in women and 25-fold in men over 20 years, and 38-fold and 173-fold when the TSH was also raised; with a normal TSH below 2.5 only 12 percent of antibody-positive women were hypothyroid 13 years later. Thyroid hormone did not improve live births in antibody-positive women with normal function, and selenium lowered titers without proven clinical benefit.

035100200

  1. Common laboratory negative range

    0 to 35 IU/mL · Typical US laboratories; D'Aurizio 2015 (manufacturer cutoffs 3.2 to 35)

  2. Below the cutoff that best predicted later hypothyroidism

    0 to 29 IU/mL · Walsh 2010

  3. Positive: a marker of autoimmune thyroiditis; the TSH decides what it means

    35 to 121 IU/mL · Pearce 2013; Garber 2012; Walsh 2010

  4. Above 121: predicted thyroiditis on histology and a higher symptom load in one surgical cohort

    121 and above IU/mL · Ott 2011

  • Laboratory range
  • Evidence supports
  • Guideline goal or unstudied
  • Higher risk in studies
Scale in IU/mL. IU/mL is the same as kIU/L. The positive cutoff depends on the assay, from about 3 to about 35 IU/mL. Bands show where studies found something, not a recommendation for any one person.

02 · What it is

What TPO antibodies measures.

Thyroid peroxidase is the enzyme involved in thyroid hormone synthesis, and it was first identified as the 'thyroid microsomal antigen', the target of the antibodies found in autoimmune thyroid disease, before its job in the gland was understood. The antibodies against it are high-affinity IgG antibodies that recognize a small immunodominant region on the intact, folded enzyme. Most of them form in response to the enzyme as it sits on thyroid cells, not to enzyme released from damaged cells, which is one reason a positive test marks an immune process rather than a quantity of injury.1,2Grade C

In the NHANES III survey of 17,353 Americans aged 12 and older, TPO antibodies were positive in 11.3 percent. They were more prevalent in women than men, increased with age, and were less prevalent in Black Americans (4.5 percent) than in white Americans (12.3 percent). In the same survey hypothyroidism of any degree was present in 4.6 percent, so most people with a positive antibody had a normal TSH. TPO antibodies were significantly associated with hypothyroidism or hyperthyroidism; thyroglobulin antibodies without them were not.3Grade B

The antibodies arrive years before the diagnosis. In 522 women in the US military with stored serum, those later diagnosed with Hashimoto's thyroiditis had TPO antibodies in about 66 percent of samples at every time point back to 7 years before diagnosis; in those later diagnosed with Graves' disease the prevalence rose from 31 percent at 5 to 7 years before diagnosis to 57 percent at diagnosis. A positive antibody in a person who feels well is therefore a true early finding, and its significance is set by what the TSH does over the following years.4Grade C

03 · Origins

Where it came from, and where it sits in the network.

The enzyme is older than the gland, and older than the immune system that attacks it. Thyroid peroxidase belongs to the animal heme peroxidase family alongside myeloperoxidase, eosinophil peroxidase and lactoperoxidase, enzymes that participate in host defense against infection; the family shares a catalytic domain of about 500 amino acids, has a bacterial member, and in a reconstruction of the whole peroxidase-cyclooxygenase superfamily its predecessor genes had already segregated very early in evolution. Before organisms developed acquired immunity, their antimicrobial defense depended on enzymes like these, recruited to produce antimicrobial reaction products. The thyroid borrowed one of them to do its chemistry: putting iodine onto tyrosine is an oxidation, and the enzyme the gland uses is a repurposed weapon of innate immunity.5,6Grade C

The borrowing predates vertebrates. Sea squirts and amphioxus, our closest invertebrate relatives, concentrate iodine in a groove under the pharynx called the endostyle, which is taken as the homolog of the follicular thyroid; in two ascidian species the thyroid peroxidase gene is expressed only in zone 7 of that organ, the region that concentrates iodine, the first gene-level evidence of a shared function between part of the endostyle and the vertebrate thyroid. That ancestry bears on why the enzyme is an autoimmune target. Thyroid peroxidase, thyroglobulin and the TSH receptor have unusual properties that contribute to breaking immune tolerance: size, abundance, membrane association, glycosylation and polymorphisms. In animal models tolerance to the TSH receptor is set in the thymus, while tolerance to thyroid peroxidase and thyroglobulin is not, and the human antibodies recognize the regions of the enzyme that are homologous to myeloperoxidase, the immune enzyme it descends from.7,8,2Grade C

Why thyroid autoimmunity appears to be rising is argued, and the two leading explanations are hypotheses, not findings. The hygiene hypothesis holds that the falling incidence of infections in Western countries, and more recently in developing ones, is at the origin of rising autoimmune and allergic disease; it rests on epidemiology, especially migration studies, which show correlation and do not prove a causal link, with proof of principle coming from animal models. The iodine hypothesis is better tested in the thyroid: across three Chinese regions with mildly deficient, more than adequate and excessive iodine intake, five-year incidence of autoimmune thyroiditis was 0.2, 1.0 and 1.3 percent, and in Denmark the prevalence of TPO antibodies above 30 U/mL rose from 14.3 to 23.8 percent within four to five years of a cautious salt iodization program, most of all in young women and at low titers. A review of incidence studies since 1950 found autoimmune thyroid disease more common than in historic series but judged the studies too variable in design, population and laboratory method to say whether the rise is real.9,10,11,12Grade C

In the network the antibody is a flag, not a gauge. It says the immune system has engaged the gland; it does not say how much hormone the gland is making. Function is read from TSH, free T4 and free T3, and the antibody changes what those numbers are likely to do next: in a cohort of 4,204 euthyroid Iranian adults followed six years, TSH, free T4, TPO antibody level, sex and smoking predicted conversion to thyroid dysfunction, and in 790 Dutch women with a relative with autoimmune thyroid disease the progression to overt hypothyroidism was gradual over years while hyperthyroidism arrived within months. The same immune tendency shows up elsewhere: about 1.6 percent of 6,024 people with autoimmune thyroid disease had biopsy-confirmed celiac disease, and in type 1 diabetes the risk of thyroid dysfunction was 25 times higher in those with thyroid autoimmunity than those without. A positive TPO antibody therefore belongs beside a TSH, and sometimes beside a question about other autoimmunity.13,14,15,16Grade B

04 · The laboratory range

What a laboratory calls normal.

Negative below about 9 to 35 IU/mL, most often below about 34 or 35, depending on the assay.

There is no single cutoff. In a multicenter comparison of automated third-generation assays, all calibrated against the same international reference preparation, the positive thresholds proposed by the manufacturers ranged from 3.2 to 35.0 IU/mL, and results on the same sera varied by a coefficient of variation of 49.8 percent even after conversion to the same units. A result of 20 IU/mL is negative on one platform and positive on another.17Grade C

When five automated methods were run on the same 240 healthy adults under 30 with a TSH of 0.5 to 2.0 and a normal ultrasound, the derived upper reference limits ranged from 6.4 to 28.7 IU/mL in men and 6.9 to 29.0 in women, and all but one were lower than the manufacturer's stated limit. The authors traced the spread to the different thyroid peroxidase preparations coated onto each assay. The number printed next to your result is the number for that method and no other.18Grade C

The cutoff that best predicts disease is not the laboratory's cutoff. In 1,184 Western Australians followed 13 years, the optimal cutoff for predicting hypothyroidism was a TPO antibody above 29 kIU/L, against the reference-range upper limit of 35; for TSH it was above 2.5 mU/L against 4.0. The two numbers are built for different purposes: the laboratory limit describes a healthy population, the predictive cutoff describes who went on to need treatment.19Grade B

05 · The evidence

What the studies support.

The reference study is the Whickham cohort: 2,779 British adults sampled in the 1970s and followed for 20 years. The odds of developing hypothyroidism were 8 in women and 44 in men with a raised TSH alone, 8 and 25 with positive thyroid antibodies alone, and 38 and 173 with both. The probability rose with any baseline TSH above 2 mU/L and rose further when antibodies were present. The annual incidence of spontaneous hypothyroidism in women was 3.5 per 1,000 survivors; in men 0.6. The antibody mattered most when the TSH was already drifting.20Grade B

The modern replication, with automated assays, is Busselton: 1,184 Western Australians followed 13 years. In women with positive thyroid antibodies, hypothyroidism at follow-up (a TSH above 4.0 or on thyroxine) was present in 12.0 percent when the baseline TSH was 2.5 or less, 55.2 percent when it was between 2.5 and 4.0, and 85.7 percent when it was above 4.0. The authors' conclusion was that TSH cutoffs of 2.5 and 4.0, combined with antibodies, give a clinically useful estimate of long-term risk. For the common case, a positive antibody with a TSH near 1 or 2, the 13-year risk was about one in eight.19Grade B

Among people who are already euthyroid, the antibody is one of the strongest predictors of change but most people do not change. In 4,204 euthyroid adults in Tehran followed six years, 93.24 percent stayed euthyroid; annual incidence of subclinical hypothyroidism was 7.62 per 1,000 and of overt hypothyroidism 2.0 per 1,000, with TSH, free T4, TPO antibody level, sex and smoking the predictors. In 790 euthyroid Dutch women with a family history of autoimmune thyroid disease, the 38 who became overtly hypothyroid over five years already had higher TSH and lower free T4 at baseline than matched controls, and the authors describe the transition as a gradual process taking several years.13,14Grade B

Guidelines use the antibody to decide how closely to watch a raised TSH, not whether to treat a normal one. The 2013 European Thyroid Association guideline says an initially raised TSH with a normal free T4 should be investigated with a repeat TSH and free T4 along with TPO antibodies, preferably after a 2- to 3-month interval, with replacement recommended in younger people once the TSH is above 10 mU/L. The 2012 American guideline says the decision to treat a subclinical hypothyroidism with a TSH below 10 should be tailored to the individual. Neither recommends treating an antibody with a normal TSH.21,22Grade A

In pregnancy the antibody is associated with worse outcomes even when thyroid function is normal. Pooling 19 cohort studies of 12,126 women, thyroid autoantibodies carried 3.90 times the odds of miscarriage (1.80 in case-control studies) and 2.07 times the odds of preterm birth. The larger individual-participant analysis of 47,045 pregnant women from 19 cohorts, 7.5 percent of them TPO antibody positive, found preterm birth in 6.6 percent of antibody-positive versus 4.9 percent of antibody-negative women, an absolute difference of 1.6 percentage points and an odds ratio of 1.33.23,24Grade A

The treatment trial was null. In TABLET, 19,585 women in 49 British hospitals were screened and 952 euthyroid women with TPO antibodies and a history of miscarriage or infertility were randomized to thyroid hormone or placebo from before conception to the end of pregnancy. Live birth after 34 weeks occurred in 37.4 percent on treatment and 37.9 percent on placebo (relative risk 0.97), with no difference in pregnancy loss, preterm birth or neonatal outcomes. The 2011 meta-analysis had pooled two small trials suggesting a 52 percent fall in miscarriage; the large trial did not confirm it. Pregnancy care in antibody-positive women is governed by the American Thyroid Association's pregnancy guideline, revised in 2017 and again in 2026, and nothing on this page replaces it.25,23,26,27Grade B

After a birth the antibody predicts thyroiditis. Pooling 21 studies of 8,081 women, postpartum thyroid dysfunction occurred in 8.1 percent of women in general and was 5.7 times as likely in women with TPO antibodies, with individual risk ratios between 4 and 97; in the United States the prevalence was 5.7 percent. Up to 50 percent of women who are thyroid antibody positive in the first trimester develop postpartum thyroiditis, and long-term follow-up of women who had an episode shows a 20 to 40 percent incidence of permanent hypothyroidism.28,29Grade B

Whether the antibody itself causes symptoms in people with a normal TSH is unresolved and the evidence is weaker than its popularity. In 426 euthyroid Austrian women having thyroid surgery for benign goiter, those with an antibody above 121 IU/mL (the cutoff that best predicted thyroiditis on histology) reported 6.7 symptoms on average against 4.1 in the rest, with no difference in TSH (1.7 versus 1.5), and chronic fatigue, dry hair, irritability and lower quality of life were more common. A systematic review of 30 studies found that 5 of 7 disease-based and 16 of 23 population-based studies reported an association between thyroid autoimmunity and symptoms or lower quality of life in biochemically euthyroid people, but the outcome measures were too different to pool, and the authors called for a randomized trial of immune-directed treatment to test causality. Nothing has shown that lowering the titer relieves the symptoms.30,31Grade C

06 · What moves it

The levers with evidence behind them.

What is listed here has been tested. The size of each effect, and the size of the study, are in the sentence, so a small effect reads as a small effect.

  • Selenium

    lowers the titer in trials; no proven effect on TSH, symptoms or progression

    In the first blinded trial, 70 women with autoimmune thyroiditis and antibodies above 350 IU/mL took 200 µg of sodium selenite or placebo for three months; mean TPO antibody fell to 63.6 percent of baseline on selenium against 88 percent on placebo, and nine selenium-treated women normalized their antibodies against two on placebo, while TSH, free T4 and free T3 were unchanged in both groups. Pooling 16 controlled trials, selenium lowered TPO antibodies by a weighted mean of 271 IU/mL at three months in people on thyroid hormone and 512 IU/mL in untreated people, with the quality of evidence generally low and more adverse effects reported on selenium. A companion meta-analysis of the clinically relevant outcomes found no change in TSH, quality of life or thyroid ultrasound in untreated patients. The titer moves; nothing that matters to the person has yet been shown to move with it.32,33,34Grade B

  • Iodine

    more raises the prevalence of antibodies once intake is adequate

    Across three Chinese regions with median urinary iodine of 84, 243 and 651 µg/L, the five-year incidence of autoimmune thyroiditis was 0.2, 1.0 and 1.3 percent and of subclinical hypothyroidism 0.2, 2.6 and 2.9 percent, and among euthyroid people who already had antibodies the incidence of a raised TSH was greater with more than adequate or excessive intake. In Denmark, bringing a mildly deficient population (median urinary iodine 61 µg/L) to a low recommended level (101 µg/L) through salt iodization was followed within four to five years by a rise in TPO antibody prevalence from 14.3 to 23.8 percent, odds ratio 1.80, most pronounced in young women and at low titers. High-dose iodine supplements and kelp are the common ways to overshoot.10,11Grade B

  • Smoking and stopping

    smokers have fewer antibodies; quitting is followed by more

    The association runs the opposite way from almost every other harm of smoking. In 15,592 Americans in NHANES III, 11 percent of smokers (by blood cotinine) had thyroid autoantibodies against 18 percent of nonsmokers, 13 percent after adjustment, and among people with antibodies smokers had 40 percent lower odds of a raised TSH. In 521 euthyroid antibody-negative Dutch women followed five years, 14.5 percent developed TPO antibodies; current smoking carried an odds ratio of 0.59 for developing antibodies at the time of seroconversion, and smoking had declined among the women who converted, so stopping was associated with the appearance of antibodies. This is an observation about immune biology, not an argument for smoking: the same NHANES analysis found smokers twice as likely to have a low-normal TSH, and the cardiovascular and cancer harms dwarf any thyroid effect.35,36Grade B

  • Pregnancy and the postpartum year

    the year after a birth is when antibody-positive women most often develop thyroiditis

    Postpartum thyroiditis is autoimmune thyroid disease arising in the first year after delivery; it is 5.7 times as likely in women with TPO antibodies, and up to half of women who are antibody positive in the first trimester develop it. In the Dutch cohort, the women who became overtly hypothyroid were more often in the postpartum period than their controls. An antibody known before or during pregnancy is a reason for thyroid testing in the postpartum year.28,29,14Grade B

  • Vitamin D

    low levels travel with the antibody; supplements lowered titers in small trials, with unknown clinical meaning

    Across 20 case-control studies, people with autoimmune thyroid disease had lower 25-hydroxyvitamin D than controls (standardized mean difference -0.99) and were 2.99 times as likely to be deficient; that is association, and reverse causation and shared lifestyle are not excluded. Six randomized trials with 344 participants found that vitamin D supplementation lowered TPO antibody titers at six months (standardized mean difference -1.11) but not within three months, with no serious adverse effects and no clinical outcome measured. Whether correcting a low vitamin D changes anything about the thyroid is unknown.37,38Grade C

  • Gluten-free diet

    lowered titers in one small unrandomized study of women who also had celiac antibodies

    The evidence is thin. In 34 Polish women with Hashimoto's thyroiditis and incidentally positive tissue transglutaminase antibodies, 16 who followed a gluten-free diet for six months had lower thyroid antibody titers and a small rise in 25-hydroxyvitamin D while 18 who did not had no change; the groups were not randomized and no change in TSH or free hormones was reported. Every participant had the serological marker of celiac disease, so the result says nothing about gluten in people without it. What is better established is the overlap itself: about 1.6 percent of people with autoimmune thyroid disease, about 1 in 62, have biopsy-confirmed celiac disease, which is an argument for testing for celiac disease, not for an untested diet.39,15Grade C

  • Inheritance

    sets most of the tendency; the levers above work on the remainder

    In 1,372 healthy Danish twins, genetic factors accounted for 73 percent of the liability to being thyroid antibody positive, and 61 percent (men) to 72 percent (women) of the variation in TPO antibody concentration after adjustment for age and TSH. The susceptibility genes identified so far include immune-modifying genes such as the human leukocyte antigen region and cytotoxic T lymphocyte antigen-4, and thyroid-specific genes such as the TSH receptor and thyroglobulin, several shared between Graves' disease and Hashimoto's thyroiditis. A positive antibody in a person whose mother and sister have thyroid disease is the expected finding, not a mystery to be solved with supplements.40,41Grade C

07 · Reading it well

Caveats, and what belongs with a physician.

'Positive' and 'negative' are properties of the assay as much as of the person. Manufacturer cutoffs on current automated platforms span 3.2 to 35.0 IU/mL, and the same healthy reference group produced upper limits from about 6 to about 29 IU/mL across five methods. A low-positive result on one platform may be negative on another, and a result should be compared only with earlier results from the same laboratory and method.17,18Grade C

The titer is not a disease activity score. Antibodies were present at a steady prevalence for seven years before a diagnosis of Hashimoto's thyroiditis in military women, so a high number does not mean the gland is about to fail, and in the selenium trials the titer fell by hundreds of IU/mL while TSH, hormones and quality of life did not change. Trends in TSH and free T4 over time, not trends in the titer, are what track function.4,34,33Grade B

A positive antibody with a normal TSH is common and usually stays that way for years. In the Australian cohort, 88 percent of antibody-positive women with a TSH of 2.5 or less were still not hypothyroid 13 years later; in the Iranian cohort 93 percent of euthyroid adults were still euthyroid after six years. The antibody raises a probability; it does not set a date.19,13Grade B

Antibodies can appear and, less often, disappear. Among 521 antibody-negative women with an affected relative, 14.5 percent developed TPO antibodies within five years, so a single negative result in a person with a strong family history is a snapshot rather than a clearance. The reverse also happened in trials: nine of 36 women on selenium and two of 34 on placebo normalized their antibodies within three months, which says that a titer can fall below the cutoff without anyone knowing what it means.36,32Grade C

Pregnancy has its own guideline. Thyroid autoantibodies and pregnancy complications, thyroid considerations in infertile women and postpartum thyroid dysfunction each have their own recommendations in the American Thyroid Association's pregnancy guideline, and the one large randomized trial in this area was null. Nothing on this page applies to a pregnant reader or one planning a pregnancy.26,27,25Grade A

See a physician

  • Positive TPO antibodies with a TSH above the laboratory range on any draw, or with a TSH below it, which is the combination the guidelines are written for.
  • Positive antibodies while pregnant, trying to conceive, going through fertility treatment, or in the year after a birth, where the risk of thyroiditis and the monitoring schedule are set by the pregnancy guideline.
  • A visibly enlarged thyroid, a lump in the neck, difficulty swallowing, or hoarseness that does not resolve, whatever the antibody or the TSH.
  • Symptoms of hypothyroidism, such as fatigue, cold intolerance, constipation, dry skin or hair loss, together with positive antibodies and a TSH in the upper part of the range, where the Busselton odds of progression justify a plan for how often to recheck.
  • Positive antibodies alongside symptoms of another autoimmune condition, such as unexplained diarrhea, weight loss or anemia (celiac disease) or new thirst and urination (type 1 diabetes), which travel with thyroid autoimmunity.
  • Positive antibodies in a person taking a medicine known to unsettle the thyroid (certain mood stabilizers, heart-rhythm drugs, interferons and cancer immunotherapies) or high-dose iodine, each of which can convert a quiet autoimmunity into thyroid dysfunction; the prescriber should know the antibody result.

This page is education, not individual medical advice, and reading it creates no physician-patient relationship.

08 · Open questions

What the literature does not settle.

  • No trial has shown that lowering a TPO antibody titer, by selenium, vitamin D, diet or anything else, changes progression to hypothyroidism, symptoms or any outcome a person would notice; the Danish CATALYST trial was designed to test selenium against thyroid-related quality of life in 472 people, and its answer will be the first real test.
  • Whether the antibody itself causes the fatigue and lower quality of life reported by euthyroid people who carry it, or whether both reflect something else, is unresolved; the systematic review of 30 studies could not pool them and no interventional trial exists.
  • Whether to screen for TPO antibodies, in the general population, before pregnancy, or in infertility, is unsettled; the large pregnancy trial of treatment was null, which weakens the case for screening to treat, while the postpartum thyroiditis risk still argues for knowing.
  • Diet claims, gluten-free diets in particular, rest on one small unrandomized study of women who all carried celiac antibodies; no randomized trial of any diet has measured thyroid outcomes in antibody-positive people without celiac disease.
  • The assays still disagree by several-fold on where 'positive' begins, and an international effort to harmonize thyroid peroxidase antigen preparations has not yet produced a single cutoff.

10

Questions

11 · Sources

41 sources, read in full.

Numbered in the order they appear. Each line says what this page relies on from the paper; the link opens the record at PubMed or the publisher.

  1. 1.

    Ruf J, Carayon P. Structural and functional aspects of thyroid peroxidase. Archives of Biochemistry and Biophysics. 2006. PMID 16098474. DOI 10.1016/j.abb.2005.06.023.

    Review · Thyroperoxidase is the enzyme of thyroid hormone synthesis and was first identified as the thyroid microsomal antigen of autoimmune thyroid disease.

  2. 2.

    McLachlan SM, Rapoport B. Thyroid peroxidase as an autoantigen. Thyroid. 2007. PMID 17822378. DOI 10.1089/thy.2007.0169.

    Review · TPO evokes high-affinity IgG autoantibodies to an immunodominant region on intact TPO, in the regions homologous to myeloperoxidase; most autoantibodies develop in response to TPO presented by thyroid cells rather than released from damaged cells.

  3. 3.

    Hollowell JG, Staehling NW, Flanders WD, Hannon WH, Gunter EW, Spencer CA, Braverman LE. Serum TSH, T(4), and thyroid antibodies in the United States population (1988 to 1994): National Health and Nutrition Examination Survey (NHANES III). Journal of Clinical Endocrinology and Metabolism. 2002. PMID 11836274. DOI 10.1210/jcem.87.2.8182.

    Cross-sectional study · In 17,353 Americans, TPO antibodies positive in 11.3 percent, more in women, rising with age, 4.5 percent in Black and 12.3 percent in white Americans; hypothyroidism 4.6 percent; TPOAb associated with thyroid dysfunction, TgAb alone not.

  4. 4.

    Hutfless S, Matos P, Talor MV, Caturegli P, Rose NR. Significance of prediagnostic thyroid antibodies in women with autoimmune thyroid disease. Journal of Clinical Endocrinology and Metabolism. 2011. PMID 21715532. DOI 10.1210/jc.2011-0228.

    Prospective cohort · In 522 military women, TPO antibodies were present in about 66 percent of later Hashimoto's cases at all time points up to 7 years before diagnosis, and rose from 31 to 57 percent before Graves' disease.

  5. 5.

    Daiyasu H, Toh H. Molecular evolution of the myeloperoxidase family. Journal of Molecular Evolution. 2000. PMID 11080366. DOI 10.1007/s002390010106.

    Review · Myeloperoxidase, eosinophil peroxidase, thyroid peroxidase, lactoperoxidase and others share a catalytic domain of about 500 residues; 60 sequences in 16 subfamilies, including the first bacterial member.

  6. 6.

    Zamocky M, Jakopitsch C, Furtmüller PG, Dunand C, Obinger C. The peroxidase-cyclooxygenase superfamily: Reconstructed evolution of critical enzymes of the innate immune system. Proteins. 2008. PMID 18247411. DOI 10.1002/prot.21950.

    Review · Predecessor genes of mammalian heme peroxidases segregated very early in evolution; before acquired immunity, antimicrobial defense depended on such enzymes, which became components of innate immunity.

  7. 7.

    Ogasawara M, Di Lauro R, Satoh N. Ascidian homologs of mammalian thyroid peroxidase genes are expressed in the thyroid-equivalent region of the endostyle. Journal of Experimental Zoology. 1999. PMID 10440727. DOI 10.1002/(sici)1097-010x(19990815)285:2<158::aid-jez8>3.0.co;2-0.

    Laboratory method study · In two ascidians, TPO gene expression was restricted to zone 7 of the endostyle, the iodine-concentrating region homologous to the vertebrate follicular thyroid.

  8. 8.

    McLachlan SM, Rapoport B. Breaking tolerance to thyroid antigens: changing concepts in thyroid autoimmunity. Endocrine Reviews. 2014. PMID 24091783. DOI 10.1210/er.2013-1055.

    Review · TSHR, TPO and Tg have unusual immunogenic properties (size, abundance, membrane association, glycosylation, polymorphisms); intrathymic expression controls tolerance to the TSHR but not TPO or Tg; most environmental factors including excess iodine reveal rather than induce thyroid autoimmunity.

  9. 9.

    Okada H, Kuhn C, Feillet H, Bach JF. The 'hygiene hypothesis' for autoimmune and allergic diseases: an update. Clinical and Experimental Immunology. 2010. PMID 20415844. DOI 10.1111/j.1365-2249.2010.04139.x.

    Review · The hygiene hypothesis attributes rising autoimmune and allergic disease to falling infections; it rests on epidemiology and migration studies that show correlation without proving causation, with proof of principle from animal models.

  10. 10.

    Teng W, Shan Z, Teng X, et al.. Effect of iodine intake on thyroid diseases in China. New England Journal of Medicine. 2006. PMID 16807415. DOI 10.1056/NEJMoa054022.

    Prospective cohort · Across regions with median urinary iodine 84, 243 and 651 µg/L, five-year incidence of autoimmune thyroiditis was 0.2, 1.0 and 1.3 percent and of subclinical hypothyroidism 0.2, 2.6 and 2.9 percent; among euthyroid antibody-positive people, raised TSH was more frequent with higher intake.

  11. 11.

    Pedersen IB, Knudsen N, Carlé A, et al.. A cautious iodization programme bringing iodine intake to a low recommended level is associated with an increase in the prevalence of thyroid autoantibodies in the population. Clinical Endocrinology. 2011. PMID 21521277. DOI 10.1111/j.1365-2265.2011.04008.x.

    Cross-sectional study · Before (n 4,649, urinary iodine 61 µg/L) and 4 to 5 years after (n 3,570, 101 µg/L) Danish salt iodization, TPO antibodies above 30 U/mL rose from 14.3 to 23.8 percent, odds ratio 1.80, most in young women and at low titers.

  12. 12.

    McLeod DS, Cooper DS. The incidence and prevalence of thyroid autoimmunity. Endocrine. 2012. PMID 22644837. DOI 10.1007/s12020-012-9703-2.

    Review · Incidence of autoimmune thyroid disease is higher than in historic series, but studies vary so much in design, population, definition and laboratory method that it is impossible to tell whether the difference is real.

  13. 13.

    Amouzegar A, Ghaemmaghami Z, Beigy M, et al.. Natural Course of Euthyroidism and Clues for Early Diagnosis of Thyroid Dysfunction: Tehran Thyroid Study. Thyroid. 2017. PMID 28071990. DOI 10.1089/thy.2016.0409.

    Prospective cohort · In 4,204 euthyroid adults followed six years, 93.24 percent stayed euthyroid; annual incidence of subclinical hypothyroidism 7.62 and overt 2.0 per 1,000; TSH, free T4, TPO antibody level, sex and smoking predicted conversion.

  14. 14.

    Effraimidis G, Strieder TG, Tijssen JG, Wiersinga WM. Natural history of the transition from euthyroidism to overt autoimmune hypo- or hyperthyroidism: a prospective study. European Journal of Endocrinology. 2011. PMID 20956436. DOI 10.1530/EJE-10-0785.

    Prospective cohort · In 790 euthyroid women with an affected relative followed five years, the 38 who became overtly hypothyroid already had higher TSH and lower free T4 at baseline; progression to hypothyroidism is gradual over years, hyperthyroidism develops in months; hypothyroid cases were more often postpartum.

  15. 15.

    Roy A, Laszkowska M, Sundström J, et al.. Prevalence of Celiac Disease in Patients with Autoimmune Thyroid Disease: A Meta-Analysis. Thyroid. 2016. PMID 27256300. DOI 10.1089/thy.2016.0108.

    Systematic review and meta-analysis · Pooled across 6,024 patients with autoimmune thyroid disease, biopsy-confirmed celiac disease was present in 1.6 percent, about 1 in 62; higher in children (6.2 percent).

  16. 16.

    Shun CB, Donaghue KC, Phelan H, Twigg SM, Craig ME. Thyroid autoimmunity in Type 1 diabetes: systematic review and meta-analysis. Diabetic Medicine. 2014. PMID 24103027. DOI 10.1111/dme.12318.

    Systematic review and meta-analysis · Across 14 studies of 2,972 young people and 789 adults with type 1 diabetes, the risk of thyroid dysfunction was 25 times higher in those with thyroid autoimmunity.

  17. 17.

    D'Aurizio F, Tozzoli R, Villalta D, Pesce G, Bagnasco M. Immunoassay of thyroid peroxidase autoantibodies: diagnostic performance in automated third generation methods. A multicentre evaluation. Clinical Chemistry and Laboratory Medicine. 2015. PMID 25274951. DOI 10.1515/cclm-2014-0545.

    Laboratory method study · Across automated third-generation TPOAb assays calibrated to the same reference preparation, between-method variability was 49.8 percent after unit conversion and manufacturers' positive thresholds ranged from 3.2 to 35.0 IU/mL.

  18. 18.

    D'Aurizio F, Metus P, Polizzi Anselmo A, et al.. Establishment of the upper reference limit for thyroid peroxidase autoantibodies according to the guidelines proposed by the National Academy of Clinical Biochemistry: comparison of five different automated methods. Auto-Immunity Highlights. 2015. PMID 26275915. DOI 10.1007/s13317-015-0070-x.

    Laboratory method study · In 120 healthy men and 120 women under 30 with TSH 0.5 to 2.0, upper reference limits across five methods ranged from 6.4 to 28.7 IU/mL (men) and 6.9 to 29.0 (women), lower than the manufacturers' limits in all but one case.

  19. 19.

    Walsh JP, Bremner AP, Feddema P, Leedman PJ, Brown SJ, O'Leary P. Thyrotropin and thyroid antibodies as predictors of hypothyroidism: a 13-year, longitudinal study of a community-based cohort using current immunoassay techniques. Journal of Clinical Endocrinology and Metabolism. 2010. PMID 20097710. DOI 10.1210/jc.2009-1977.

    Prospective cohort · In 1,184 Busselton adults followed 13 years, optimal predictive cutoffs were TSH above 2.5 and TPOAb above 29 kIU/L; in antibody-positive women hypothyroidism at follow-up was 12.0 percent with TSH 2.5 or less, 55.2 percent at 2.5 to 4.0 and 85.7 percent above 4.0.

  20. 20.

    Vanderpump MP, Tunbridge WM, French JM, et al.. The incidence of thyroid disorders in the community: a twenty-year follow-up of the Whickham Survey. Clinical Endocrinology. 1995. PMID 7641412. DOI 10.1111/j.1365-2265.1995.tb01894.x.

    Prospective cohort · Over 20 years in 2,779 adults, odds of hypothyroidism were 8 (women) and 44 (men) with raised TSH alone, 8 and 25 with antibodies alone, 38 and 173 with both; incidence of spontaneous hypothyroidism 3.5 per 1,000 women and 0.6 per 1,000 men per year; probability rose with TSH above 2 mU/L.

  21. 21.

    Pearce SH, Brabant G, Duntas LH, Monzani F, Peeters RP, Razvi S, Wemeau JL. 2013 ETA Guideline: Management of Subclinical Hypothyroidism. European Thyroid Journal. 2013. PMID 24783053. DOI 10.1159/000356507.

    Guideline · An initially raised TSH with normal free T4 should be repeated with TPO antibodies after 2 to 3 months; replacement recommended for younger patients with TSH above 10 mU/L; a wait-and-see strategy for the oldest old with TSH of 10 or less.

  22. 22.

    Garber JR, Cobin RH, Gharib H, et al.; American Association of Clinical Endocrinologists and American Thyroid Association Taskforce on Hypothyroidism in Adults. Clinical practice guidelines for hypothyroidism in adults: cosponsored by the American Association of Clinical Endocrinologists and the American Thyroid Association. Endocrine Practice. 2012. PMID 23246686. DOI 10.4158/EP12280.GL.

    Guideline · Serum TSH is the single best screening test for primary thyroid dysfunction; the decision to treat subclinical hypothyroidism with TSH below 10 mIU/L should be tailored to the individual.

  23. 23.

    Thangaratinam S, Tan A, Knox E, Kilby MD, Franklyn J, Coomarasamy A. Association between thyroid autoantibodies and miscarriage and preterm birth: meta-analysis of evidence. BMJ. 2011. PMID 21558126. DOI 10.1136/bmj.d2616.

    Systematic review and meta-analysis · Across 31 studies of 12,126 women, thyroid autoantibodies carried odds ratio 3.90 for miscarriage in cohorts (1.80 in case-control studies) and 2.07 for preterm birth; two small trials suggested a 52 percent relative reduction in miscarriage with levothyroxine.

  24. 24.

    Consortium on Thyroid and Pregnancy, Study Group on Preterm Birth; Korevaar TIM, Derakhshan A, Taylor PN, et al.. Association of Thyroid Function Test Abnormalities and Thyroid Autoimmunity With Preterm Birth: A Systematic Review and Meta-analysis. JAMA. 2019. PMID 31429897. DOI 10.1001/jama.2019.10931.

    Systematic review and meta-analysis · Individual data on 47,045 pregnant women from 19 cohorts, 7.5 percent TPOAb positive: preterm birth 6.6 versus 4.9 percent, absolute difference 1.6 percent, odds ratio 1.33.

  25. 25.

    Dhillon-Smith RK, Middleton LJ, Sunner KK, et al.. Levothyroxine in Women with Thyroid Peroxidase Antibodies before Conception. New England Journal of Medicine. 2019. PMID 30907987. DOI 10.1056/NEJMoa1812537.

    Randomized trial · TABLET: 19,585 women screened, 952 euthyroid TPOAb-positive women with miscarriage or infertility randomized; live birth after 34 weeks 37.4 percent on levothyroxine versus 37.9 percent on placebo (relative risk 0.97), no difference in pregnancy loss, preterm birth or neonatal outcomes.

  26. 26.

    Alexander EK, Pearce EN, Brent GA, et al.. 2017 Guidelines of the American Thyroid Association for the Diagnosis and Management of Thyroid Disease During Pregnancy and the Postpartum. Thyroid. 2017. PMID 28056690. DOI 10.1089/thy.2016.0457.

    Guideline · Recommendations on thyroid autoantibodies and pregnancy complications, thyroid considerations in infertile women, hypothyroidism in pregnancy, postpartum care and screening.

  27. 27.

    Korevaar TIM, Leung AM, Alexander EK, et al.. American Thyroid Association 2026 Guidelines for Thyroid Disease in Preconception, Pregnancy, and Postpartum. Thyroid. 2026. PMID 42219800. DOI 10.1177/10507256261445624.

    Guideline · The current ATA guideline, with recommendations on thyroid autoimmunity, hypothyroidism and postpartum thyroid dysfunction for women with infertility, pregnant women and women postpartum; much of the evidence rated low to moderate quality.

  28. 28.

    Nicholson WK, Robinson KA, Smallridge RC, Ladenson PW, Powe NR. Prevalence of postpartum thyroid dysfunction: a quantitative review. Thyroid. 2006. PMID 16839259. DOI 10.1089/thy.2006.16.573.

    Systematic review and meta-analysis · Across 21 studies of 8,081 women, postpartum thyroid dysfunction 8.1 percent overall and 5.7 percent in the United States; pooled risk ratio 5.7 (range 4 to 97) with TPO antibodies.

  29. 29.

    Stagnaro-Green A. Approach to the patient with postpartum thyroiditis. Journal of Clinical Endocrinology and Metabolism. 2012. PMID 22312089. DOI 10.1210/jc.2011-2576.

    Review · Postpartum thyroiditis incidence 5.4 percent; up to 50 percent of women thyroid antibody positive in the first trimester develop it; 20 to 40 percent later have permanent hypothyroidism.

  30. 30.

    Ott J, Promberger R, Kober F, et al.. Hashimoto's thyroiditis affects symptom load and quality of life unrelated to hypothyroidism: a prospective case-control study in women undergoing thyroidectomy for benign goiter. Thyroid. 2011. PMID 21186954. DOI 10.1089/thy.2010.0191.

    Prospective cohort · In 426 euthyroid women having thyroid surgery, anti-TPO above 121 IU/mL predicted histological thyroiditis; those above it reported 6.7 versus 4.1 symptoms with no TSH difference (1.7 versus 1.5) and lower quality of life.

  31. 31.

    Groenewegen KL, Mooij CF, van Trotsenburg ASP. Persisting symptoms in patients with Hashimoto's disease despite normal thyroid hormone levels: Does thyroid autoimmunity play a role? A systematic review. Journal of Translational Autoimmunity. 2021. PMID 34027377. DOI 10.1016/j.jtauto.2021.100101.

    Review · Of 30 studies, 5 of 7 disease-based and 16 of 23 population-based found an association between thyroid autoimmunity and symptoms or lower quality of life in euthyroid people; outcomes too heterogeneous to pool; a randomized trial of immunomodulation is needed to test causality.

  32. 32.

    Gärtner R, Gasnier BC, Dietrich JW, Krebs B, Angstwurm MW. Selenium supplementation in patients with autoimmune thyroiditis decreases thyroid peroxidase antibodies concentrations. Journal of Clinical Endocrinology and Metabolism. 2002. PMID 11932302. DOI 10.1210/jcem.87.4.8421.

    Randomized trial · In 70 women with antibodies above 350 IU/mL, 200 µg sodium selenite for 3 months lowered mean TPOAb to 63.6 percent of baseline versus 88 percent on placebo; 9 versus 2 normalized; TSH, free T4 and free T3 unchanged.

  33. 33.

    Wichman J, Winther KH, Bonnema SJ, Hegedüs L. Selenium Supplementation Significantly Reduces Thyroid Autoantibody Levels in Patients with Chronic Autoimmune Thyroiditis: A Systematic Review and Meta-Analysis. Thyroid. 2016. PMID 27702392. DOI 10.1089/thy.2016.0256.

    Systematic review and meta-analysis · Across 16 controlled trials, selenium lowered TPOAb by a weighted mean of 271 IU/mL at 3 months in LT4-treated and 512 IU/mL in untreated patients; quality of evidence generally low; more adverse effects on selenium; clinical relevance undemonstrated.

  34. 34.

    Winther KH, Wichman JE, Bonnema SJ, Hegedüs L. Insufficient documentation for clinical efficacy of selenium supplementation in chronic autoimmune thyroiditis, based on a systematic review and meta-analysis. Endocrine. 2017. PMID 27683225. DOI 10.1007/s12020-016-1098-z.

    Systematic review and meta-analysis · Across nine controlled trials, no effect of selenium on TSH, health-related quality of life or thyroid ultrasound in levothyroxine-untreated patients; evidence very low to moderate quality.

  35. 35.

    Belin RM, Astor BC, Powe NR, Ladenson PW. Smoke exposure is associated with a lower prevalence of serum thyroid autoantibodies and thyrotropin concentration elevation and a higher prevalence of mild thyrotropin concentration suppression in the third National Health and Nutrition Examination Survey (NHANES III). Journal of Clinical Endocrinology and Metabolism. 2004. PMID 15579761. DOI 10.1210/jc.2004-0431.

    Cross-sectional study · In 15,592 Americans, thyroid autoantibodies in 11 percent of smokers versus 18 percent of nonsmokers (13 percent adjusted); among antibody-positive people smokers had 40 percent lower odds of raised TSH; smokers had twice the odds of a low-normal TSH.

  36. 36.

    Effraimidis G, Tijssen JG, Wiersinga WM. Discontinuation of smoking increases the risk for developing thyroid peroxidase antibodies and/or thyroglobulin antibodies: a prospective study. Journal of Clinical Endocrinology and Metabolism. 2009. PMID 19141579. DOI 10.1210/jc.2008-1548.

    Prospective cohort · In 521 euthyroid antibody-negative women followed 5 years, 14.5 percent developed TPO antibodies; odds ratio for current smoking 0.59 at seroconversion; stopping smoking associated with antibody appearance.

  37. 37.

    Wang J, Lv S, Chen G, et al.. Meta-analysis of the association between vitamin D and autoimmune thyroid disease. Nutrients. 2015. PMID 25854833. DOI 10.3390/nu7042485.

    Systematic review and meta-analysis · Across 20 case-control studies, autoimmune thyroid disease patients had lower 25(OH)D (standardized mean difference -0.99) and odds ratio 2.99 for deficiency.

  38. 38.

    Wang S, Wu Y, Zuo Z, Zhao Y, Wang K. The effect of vitamin D supplementation on thyroid autoantibody levels in the treatment of autoimmune thyroiditis: a systematic review and a meta-analysis. Endocrine. 2018. PMID 29388046. DOI 10.1007/s12020-018-1532-5.

    Systematic review and meta-analysis · Six randomized trials, 344 patients: vitamin D lowered TPOAb at six months (standardized mean difference -1.11) but not within 3 months; no serious adverse effects; no clinical outcomes.

  39. 39.

    Krysiak R, Szkróbka W, Okopień B. The Effect of Gluten-Free Diet on Thyroid Autoimmunity in Drug-Naïve Women with Hashimoto's Thyroiditis: A Pilot Study. Experimental and Clinical Endocrinology and Diabetes. 2019. PMID 30060266. DOI 10.1055/a-0653-7108.

    Prospective cohort · 34 women with Hashimoto's and positive tissue transglutaminase antibodies; 16 on a gluten-free diet for 6 months had lower thyroid antibody titers and slightly higher 25(OH)D than 18 untreated; not randomized; TSH and free hormones unchanged.

  40. 40.

    Hansen PS, Brix TH, Iachine I, Kyvik KO, Hegedüs L. The relative importance of genetic and environmental effects for the early stages of thyroid autoimmunity: a study of healthy Danish twins. European Journal of Endocrinology. 2006. PMID 16381988. DOI 10.1530/eje.1.02060.

    Prospective cohort · In 1,372 healthy twins, genetic factors accounted for 73 percent of the liability to thyroid antibody positivity and 61 percent (men) to 72 percent (women) of TPOAb concentration.

  41. 41.

    Tomer Y, Davies TF. Searching for the autoimmune thyroid disease susceptibility genes: from gene mapping to gene function. Endocrine Reviews. 2003. PMID 14570752. DOI 10.1210/er.2002-0030.

    Review · Susceptibility genes for autoimmune thyroid disease include immune-modifying genes (HLA, CTLA-4) and thyroid-specific genes (TSH receptor, thyroglobulin), some shared between Graves' and Hashimoto's; family and twin studies point to strong genetic influence.

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