Natural History of Thyroid Function Disorders

Participants in this study will be patients diagnosed with or suspected to have a thyroid function disorder. These conditions may include: hypothyroidism, hyperthyroidism, thyroid hormone resistance, Graves' Dermopathy, and thyroid-stimulating hormone (TSH) secreting pituitary adenomas.

The main purpose of this study is to further understand the natural history, clinical presentation, and genetics of thyroid function disorders. Many of the tests performed are in the context of standard medical care that is offered to all patients with thyroid function disorders. In addition, blood and tissue samples may be taken for research and genetic studies....

Study Overview

• Status: Recruiting
• Conditions: Hypothyroidism; Hyperthyroidism; Grave's Disease

Detailed Description

Study Description:

Participants with known or suspected thyroid function abnormalities (hyperthyroidism, hypothyroidism, extreme iodine deficiency, and inherited forms of hypothyroidism resulting from abnormalities in the expression of genes coding for the TSH- beta subunit, Pax-8, TTF-2, Pit-I, Tg, PDS, and NIS) and/or with thyroid function tests abnormalities. Participants undergo routine examinations and other standard diagnostic procedures, as clinically indicated. Blood, urine, and leftover thyroid or pituitary tissue specimens will be collected for research.

Objectives:

1. To understand the pathophysiology and various causes of thyroid function abnormalities (e.g., hyperthyroidism, hypothyroidism).
2. To longitudinally follow the effects of standard therapies for participants with abnormal thyroid functions.
3. To create a repository of clinical data and samples for future research of thyroid disorders.

Endpoints: None

• Study Type: Observational
• Enrollment (Estimated): 2500

Contacts and Locations

• Study Contact: Name: Joanna Klubo-Gwiezdzinska, M.D.; Phone Number: (301) 496-5052; Email: joanna.klubo-gwiezdzinska@nih.gov
• Study Contact Backup: Name: Padmasree Veeraraghavan, R.N.; Phone Number: (301) 451-7710; Email: padmasree.veeraraghavan@nih.gov

Study Locations

• United States
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • Recruiting
      • National Institutes of Health Clinical Center
      • Contact: For more information at the NIH Clinical Center contact Office of Patient Recruitment (OPR); Phone Number: TTY dial 711 800-411-1222; Email: ccopr@nih.gov

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 6 months and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

anyone meeting eligibility criteria.

Description

• INCLUSION CRITERIA:

The categories of subjects eligible to participate in this study include:

1. Participants with known or suspected thyroid abnormalities (e.g. hypothyroidism, hyperthyroidism, extreme iodine deficiency, and inherited forms of hypothyroidism resulting from abnormalities in the expression of genes coding for the TSH- beta subunit, Pax-8, TTF-2, Pit-I, Tg, PDS, and NIS).

2. Participants with thyroid function test (TFT) abnormalities due to:

   • Non-thyroidal illness
   • Abnormalities of serum TH binding proteins leading to euthyroid hyperthyroxinemia or hypotriiodothyronemia.
   • Genetic deficiency of thyroxine-binding globulin (TBG).
   • Antibodies to mouse immunoglobulins leading to an artifactual elevation in the TSH ultrasensitive ("3rd generation") assay which may mimic "inappropriate" secretion of TSH.

Inclusion and exclusion criteria for each group of subjects are given below.

Participants with known or suspected thyroid abnormalities will be eligible to participate if the individual meets all of the following criteria:

1. Stated willingness to comply with all study procedures and availability for the duration of the study.
2. Male or female, aged 6 months+.

Hyperthyroid states include but are not restricted to:

1. Graves' disease (GD) thought to result from thyroid-stimulating immunoglobulins (TSIg's), a subclass of which also stimulate eye muscle and fatty tissue producing exophthalmos (Graves' ophthalmopathy), as well as the skin in the pretibial area causing pretibial myxedema (Graves' dermopathy);
2. Subacute thyroiditis (SAT), a painful inflammation thought to result from viral infection with Coxsackie, as well as other viruses;
3. Silent thyroiditis, a painless inflammation thought to result from autoimmune attack of thyrocytes by antimicrosomal antibodies directed against thyroid peroxidase (TPO), as well as antithyroglobulin(anti-Tg) antibodies;
4. Single or multiple hyperfunctioning thyroid nodules of unknown etiology, probably resulting from the activation of certain thyroid oncogenes and/or growth factors, such as the thyrotropin (TSH) receptor (TSHR) and the a-subunit of the Gs protein (Gsa);
5. Iodide-induced hyperthyroidism of unknown etiology;
6. Surreptitious administration of thyroid hormone (TH), usually present in participants with underlying psychiatric disease or occasionally related to participants with obesity and other eating disorders
7. Trophoblastic neoplasms, thought to result from high levels of hCG secretion, which, because of its structural similarity to TSH, causes "spillover" of action at the TSHR level;
8. "Inappropriate" secretion of TSH, which may be present either in participants with TSH- producing pituitary tumors (TSHomas) or from a non-neoplastic cause, i.e. pituitary resistance to the action of thyroid hormone (3,4).

The above are the principal variants of hyperthyroidism that we will study, although we may discover that certain participants may turn out to have rare causes of hyperthyroidism, e.g. unusual variants of ectopic thyroid tissue, "hyperfunctioning" thyroid cancer, choriocarcinoma, or ovarian teratomas. Finally, some participants may present with extreme thyrotoxic symptoms in the context of "thyroid storm" or, conversely, with apathetic thyrotoxicosis.

Hypothyroid states include but are not restricted to:

1. Primary (or thyroidal) hypothyroidism, usually resulting from auto-antibodies to thyroid proteins, such as antimicrosomal antibodies to TPO usually associated with lymphocytic (Hashimoto's) thyroiditis (HT) or atrophic thyroiditis, or blocking antibodies to the TSHR, usually in the context of non-goitrous hypothyroidism;
2. Secondary (or pituitary) hypothyroidism, usually resulting from tumors of the pituitary of non-thyrotropic origin such, as growth hormone (GH)-secreting tumors or prolactinomas;
3. Tertiary (or hypothalamic) hypothyroidism, usually resulting from a deficiency in the hypothalamic hormone thyrotropin-releasing hormone (TRH), either of unknown etiology or secondary to a pituitary tumor;
4. Bio-inactive TSH, either relating to an endogenous abnormality of hypothalamic hormones or secondary to pituitary tumors (and usually related to abnormal glycosylation patterns of the TSH molecule);
5. Generalized resistance to thyroid hormone (RTH), a disease which has been shown to be due to abnormalities in the TH receptor, c-erbA-beta (or TR- beta).

The above are the principal disorders under study, but we may also investigate other abnormalities, such as extreme iodine deficiency, and inherited forms of hypothyroidism resulting from abnormalities in the expression of genes coding for the TSH- beta subunit, Pax-8, TTF-2, Pit-I, Tg, PDS, and NIS (among others).

EXCLUSION CRITERIA:

There are no exclusion criteria for subjects with known or suspected thyroid abnormalities.

Study Plan

How is the study designed?

Design Details

• Observational Models: Case-Only
• Time Perspectives: Retrospective

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort
Thyroid disorders; Participants with thyroid disorders

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
evaluation of thyroid disorders	Participants undergo routine history and physical examination, standard endocrine blood and urine tests, a standard TRH test, thyroid nuclear medicine scans, thyroidal radioiodine (RAI) or technetium (99mTc) uptake measurements, as well as X-ray, computed tomography (CT) or magnetic resonance imaging (MRI) studies or other standard diagnostic procedures, as clinically indicated.	ongoing

Collaborators and Investigators

• Sponsor: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• Investigators: Principal Investigator: Joanna Klubo-Gwiezdzinska, M.D., National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Publications and helpful links

General Publications

• Szczepanek-Parulska E, Klubo-Gwiezdzinska J, Ruchala M. Editorial: Novel Imaging Techniques in the Management of Thyroid Nodules and Autoimmune Thyroid Disease. Front Endocrinol (Lausanne). 2019 Nov 20;10:804. doi: 10.3389/fendo.2019.00804. eCollection 2019. No abstract available.
• Krieger CC, Boutin A, Jang D, Morgan SJ, Banga JP, Kahaly GJ, Klubo-Gwiezdzinska J, Neumann S, Gershengorn MC. Arrestin-beta-1 Physically Scaffolds TSH and IGF1 Receptors to Enable Crosstalk. Endocrinology. 2019 Jun 1;160(6):1468-1479. doi: 10.1210/en.2019-00055.

Helpful Links

• NIH Clinical Center Detailed Web Page

Study record dates

Study Major Dates

• Study Start (Actual): February 1, 1977

Study Registration Dates

• First Submitted: November 3, 1999
• First Submitted That Met QC Criteria: November 3, 1999
• First Posted (Estimated): November 4, 1999

Study Record Updates

• Last Update Posted (Actual): September 10, 2026
• Last Update Submitted That Met QC Criteria: September 9, 2026
• Last Verified: September 8, 2026

More Information

Terms related to this study

• Keywords: Hypothyroidism; Natural History; Hyperthyroidism; Grave's Disease; Thyroid-Stimulating Hormone Secreting Pituitary Ad
• Additional Relevant MeSH Terms: Endocrine System Diseases; Thyroid Diseases; Hyperthyroidism; Hypothyroidism
• Other Study ID Numbers: 770002; 77-DK-0002

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Subject level data will be shared upon request after appropriate collaboration agreements are in place.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No