Thyroid Diseases

  1. Hyperthyroidism
    1. Hyperthyroidism results from excess levels of T3 and T4 which can be cause by several factors
    2. Classically, the patient is extremely nervous, fatigued, may show weight loss, proximal muscle wasting, eye protrusion, intolerance to heat, and pretibial myxedema
    3. Nodular goiter
    4. Signs of hyperthyroidism
    5. Autonomously functioning cells in thyroid develop and produce excessive amounts of thyroid hormones
    6. In addition, increased levels of TSH may further exacerbate this situation
      1. Heterogeneity (no longer homogeneous cell structure) and replication occurs, which form thyroid nodules over time
      2. These nodules contain hyper-functioning tissue
      3. In addition, these nodules continue to replicate, resulting in "cloned" nodule
      4. The term autonomous is important since it indicates that these nodes can still excrete excessive amounts of thyroid hormones, even when the body responds by reducing TSH levels
      5. Over time, hot and cold nodules can be noted in this disease
      6. Cold nodules may be the response to lower TSH levels, while hot nodules would be considered autonomous in nature
      7. Also, hemorrhage and necrosis of a hot nodule will result in a cold nodule

  2. Graves' Disease (toxic goiter)
    1. Symptoms: diffused enlarged gland (goiter), hyper-metabolism, exophthalmus (eyes).
    2. Long Acting Thyroid Substance (LATS) is noted in blood tests, but the reason for this is unknown
    3. TSH levels are usually low
    4. Increase levels of T3 and T4. Blood test usually indicate a high level of T4
    5. About 50% of patients that have this disorder go into remission if left untreated
    6. More theory on why this happens
      1. Patients with Graves' disease also have auto-antibodies that may be synthesized by lymphocytes in the thyroid and stimulate TSH receptor within the thyroid (there are two types)
      2.   The two types of of antibodies are: Thyroid stimulating antibody (TSAb) and anti-TSA
      3. TSAb stimulates thyroid hormone production just like TSH, which may cause Graves' disease
      4. Radioiodine therapy causes increased levels of anti-TSAb, which reverses the stimulation effect of Graves' disease
      5. Causes of Graves' disease may be due to: Yersinia enterocolitica, stress, genetic predisposition, and smoking
      6. There is also an association with some forms of thyroid cancer. In animal research, chronic TSH stimulation has shown an increased incidence in thyroid cancer

  3. Plummer's Disease
    1. Usually singular or multiple nodular (rarely) disease. The(se) functioning autonomous nodule(s) pick up excessive amounts of radioiodine
    1. Causes hyperthyroidism
    2. The anterior pituitary gland reduces the TSH levels to where there is little to no circulating TSH, however this has no effect in reducing T3/T4 production
    3. Patient produces increased levels of T3 and T4
    4. Nodule(s) usually suppress surrounding thyroid tissue
      1. Administration of TSH will determine if surrounding thyroid tissue is functioning
      2. See TSH stimulation/suppression test
      3. 201Tl and 99mTc-sestamibi are alternative radiopharmaceuticals used to see if surrounding thyroid tissue is suppressed
    5. No circulating LATS
    6. Usually requires additional 131I for treatment (as compared to Graves' disease)

  4. Toxic nodular goiter and hyperthyroidism
    1. May be single, multiple, or autonomous in nature
    1. Amount and size of nodule(s) will affect the level of hyperthyroidism
    2. Graves' or Plummer's disease may be associated with toxic nodular goiter

  5. Visit https://www.intechopen.com/books/thyroid-disorders/nuclear-medicine-in-the-assessment-of-thyrotoxicosis-associated-with-increased-thyroid-function-and- for a look at different hyperthyroid images

  6. Excessive TSH secretion causes hyperthyroidism
    1. Abnormal secretion of TSH from the pituitary gland
    1. May be due to tumor

  7. Ectopic secretion of thyroid hormone (hyperthyroidism)
    1. Teratomas and a few types of thyroid cancer secrete excess amounts of T3/T4
    1. This is rare

  8. Subacute Thyroiditis
    1. It is believed that certain types of viral infections may cause an inflammatory thyroid disorder
    1. One or more types of viruses may be associated with this process
    2. Usually the entire gland is involved, however, it may start with only part of the gland
    3. Symptoms will last for 2 weeks to several months
    4. Initial insult causes a sudden release of thyroid hormones resulting in a hyperthyroid state
    5. Thyroid uptake and scan usually indicate a hypo-activity which is caused by the initial attack/damage to the thyroid
      1. Uptake is low
      2. Impossible to image
    6. Usually thyroid function returns to normal, however, over several years, the patient may eventually become hypothyroid

  9. Postpartum Thyroiditis
    1. Seems to be an autoimmune event
    1. Pregnancy affects the immunoregulation
      1. Usually occurs in the first trimester or at delivery, with the latter being more common
      2. May recur in succeeding pregnancies
    2. There are three stages which are not always clinically present:
      1. Hyperthyroidism
      2. Hypothyroidism
      3. Euthyroidism

  10. Ingestion of thyroid hormones may cause silent thyroiditis
    1. May be caused by ingestion of beef products containing bovine rich thyroid hormones
    1. There may be other known or unknown factors
    2. It may also be an autoimmune response
    3. Usually causes transient hyperthyroidism

  11. Jod-Basedow Phenomenon
    1. Excessive intake of iodine may cause either hypo- or hyperthyroidism
    1. Refer to the thyroid's biofeedback loop, where the patient becomes hyper/hypo and finally returns to a euthyroid status
    2. Seen more frequently in places where there is iodine deficiency. In this scenario a patients with limited iodine in his/her diet resulting in an enlarged thyroid caused by increased TSH stimulation (the body is trying to extract limited iodine from the blood pool)
    3. A sudden response to a hyperactive state occurs when a significant dose of iodine is ingested
    4. This may also be seen in patient with nodular thyroid disease, where increased levels of iodine cause a hyperthyroid response

  12. Hypothyroidism
    1. Patient will appear fatigued, have cramps, and be constipated
    2. Myocardial contractility is greatly reduced, resulting in a reduction of pulse rate and stroke volume to about half of its normal value
    3. In severe cases, the patient may be in a comatose state
  13. Primary hypothyroidism (problem with the thyroid gland)
    1. Results from an iodine deficient diet; however, this is uncommon in the US
    2. In addition, thyroid failure can occur via an autoimmune response (note the above autoimmune diseases)
      1. While most autoimmune and thyroiditis initially start off as a hyper-response, eventually the patient returns to a euthyroid state; however, hypothyroidism may eventually result over time
      2. The same can be said for hyperthyroid patients being treated with 131I. Treatment usually causes hypothyroidism over time
      3. Untreated hyperthyroidism (Graves' disease as an example) shows strong indication of the gland eventually becoming hypo-active over time
    3. Drugs such as lithium and amiodarone may eventually cause the thyroid to become hypoactive
    4. In general - The inability of the thyroid gland to trap and organify iodine results in lowering iodine uptake, decreased levels of T3/T4, and elevating the levels of TSH and TRH

    14. Explain this effect using the negative biofeedback loop

  14. Secondary hypothyroidism (resulting from pituitary or hypothalamic disease)
    1. This does not occur as often as primary hypothyroidism
    2. Pituitary insufficiency maybe caused by tumor (adenoma), which results in a decrease of TSH secretion, producing a hypothyroidism
  15. Tertiary hypothyroidism (caused by hypothalamic disease)
    1. Poorly functioning hypothalamus will cause reduced secretion of TRH
    2. Insufficient TRH reduces TSH secretion, which results in a hypo-functioning gland
    3. This may occur with or without pituitary disease
  16. Autoimmune thyroiditis and Hashimoto's disease
    1. Usually results from a T-cell mediated, organ-specific autoimmune response
    2. Another words, the body attacks its own thyroid
    3. Continual insult results in fibrotic changes in the gland as well as atrophy of the follicular cells
    4. Specifically in Hashimoto's disease
      1. Anti-peroxidase antibodies attack thyroid's ability to organify iodine (peroxidase is responsible for organification)
      2. Antibodies also inhibit the peroxidase enzyme
      3. Positive perchlorate discharge test-1 is an indication of Hashimoto's disease
    5. Clinical symptoms
      1. Goiter with or without hypothyroidism
      2. May initially appear hyper-active
      3. Over time, hypothyroidism results
  17. Genetics may sometimes play a role in hypothyroidism
  18. Cretin babies are hypothyroid
    1. Appear lethargic, with potbelly and enlarged tongue
    2. Physical and mental growth are severely retarded
  19. Inflammatory (thyroiditis) - Bacterial, Viral, Autoimmune (see above disorders)
Additional comments concerning thyroid nodules
  1. Found in about 4% of the population
    1. If they accumulate iodine, it is usually considered benign
    2. Adenomas are functional and usually benign
    3. May be seen in areas where there is a low amount of Iodine in the diet
  2. Multinodular gland
    1. Nodules appear uneven with distribution of the radiotracer (combination - cold, warm, and /or hot), and are usually benign
    2. If they have a decrease (or absence) of radiotracer, ultrasound and needle aspiration are recommended
    3. If fluid is found the cold nodule is identified as a cyst
    4. If thyroid tissue is identified then thyroid cancer must be ruled out

Thyroid carcinoma

  1. Statistics
    1. Accounts for 90% of all endocrine cancers and only 1.5% of all malignancies
    2. Approximately 1000 deaths occur per year in the US
    3. Grows slowly and is more often seen young people
    4. Usually treatable
    5. Many agents other than 131I can be used to image this disease and they include: 201Tl, 99mTc-sestamibi, 131I-MIBG, 99mTc-DMSA and 18FDG

  2. General comments
    1. Thyroid carcinoma is rare but usually appears as a single solitary nodule
    1. Previous history of radiation therapy to the head and/or neck shows a higher incidence of this disease
    2. Nodule appears cold in an iodine scan
    3. Pertechnetate should not be used since a significant percentage of this cancer will appear as a hot nodule
    4. 20 to 25 % of all cold nodules are cancerous
    5. Always use ultrasound to confirm solid cold nodule
  3. A discussion on the types of thyroid cancer


    https://www.sciencedirect.com/science/article/pii/S2211568421000851

    1. Differentiated Thyroid Cancer (DTC)
      1. Papillary and Follicular Cancers (approximately 90% of all thyroid carcinomas)
      2. Iodine uptake is usually less than 10% when compared to normal thyroid tissue, which means that it may appear as a single cold nodule in the thyroid gland
      3. Distal mets may not be seen, but depends on the amount of iodine picked up by the cancerous tissue
      4. Following thyroid ablation, supplemental and before imaging if the patient is on T3, it must be discontinued for 2 weeks and if on T4 then imaging cannot occur for at least 4 to 6 weeks. This causes TSH level. Increased levels of TSH will result in increased uptake of iodine by cancerous thyroid cells.
      5. Discontinuing thyroid medication can have a very strong negative impact on the patient. It may be suggested that the patient be kept his/her medication where rhTSH is given once a day for two days at 0.9 mg this causes a rise in the TSH level which allows for 131I uptake in the cancerous cells. Better results are noted when giving rhTSH vs just stopping the patient's thyroid medication
      6. Monitoring the patients TBG level is also considered important, following ablation. Sudden increased levels of TBG is a strong indication that metastatic disease is present. FYI - TBG level should be next to zero, however, if the level increases to >2ng/ml then there is a stronger indicator that cancer is growing somewhere within the body
      7. When should the whole body 131I scan be initially done? Six to ten weeks following thyroidectomy and 2 weeks after supplemental T3 has been discontinued
        1. Note - TSH levels is >2ng/ml
        2. Pertechnetate and bone scintigraphy are usually not useful
        3. Specificity of finding disease with 131I is 95%
        4. Note - normal accumulation of radio-iodine in the salivary glands, nose, gastric mucosa, kidneys, urinary bladder, bowel, and liver may interfere with the diagnosis
        5. Scanning should be done 48 to 72 hours post administration in order to reduce the background levels of 131I in the surrounding tissues
        6. Following an ablation dose, image should not be done until 3 to 7 days post administration
      8. Use of 201Tl
        1. 201Tl has certain advantages over 131I in detecting DTC
        2. 201Tl does not have a great affinity for thyroid tissue, but has a sensitivity of 60 to 90% in detecting DTC
        3. An advantage to the patient is that supplemental thyroid medication does not have to be discontinued
        4. 99mTc-sestimibi is another agent that can be used for its detection of DTC
    1. Medullary Thyroid Carcinoma (MTC)
        1. Occurs in about 7% of thyroid cancers
        2. Does not pickup 131I, hence detection and treatment via this method is not suggested
        3. Recurrence of this disease is usually identified by measuring serum calcitonin and CEA levels
        4. Physiology of disease
          1. Tumor markers for MTC is a rise in calcitonin and carcinoembryonic antigen (CEA) 
          2. Primary arises from outer follicle walls of the thyroid gland
          3. [18F]DOPA has a high affinity for MTC and when compared to ultrasound the PET procedure was definitely more sensitive in discovering disease within lymph nodes1


          5. https://www.hindawi.com/journals/jtr/2019/1893047/

        5. Alternative methods of imaging are suggested
          1. 201Tl and 99mTc-sestamibi can be administered when the calcitonin level is at 1000 pg/ml
          2. 99mTc-DMSA has also been used which resembles the phosphate ion, which is taken up by the tumor
          3. MTC also has somatostatin sites and CEA receptors which are sensitive to68Ga-DODOTATE


        https://link.springer.com/article/10.1007/s12020-021-02709-x

      1. Thyroid Lymphoma
        1. Occurs in about 4% of thyroid malignancies
        2. Usually appears in elderly patients with a rapidly enlarging goiter
        3. Patient usually has an autoimmune lymphocytic thyroiditis
        4. Pertechnetate and 131I are not useful in detecting this disease
        5. Ultrasound, MRI, and CT are suggested
        6. In the above image 68Ga-fibroblast activation protein inhibitor (FAPI) was administered and was positive for disease
        7. 201Tl, 99mTc-sestamibi, and 67Ga may be useful diagnosing this disease


        https://www.mdpi.com/2072-6694/13/16/4228

      2. Anaplastic Carcinoma
        1. Undifferentiated and anaplastic carcinoma occur in about 5% of thyroid malignancies
        2. Usually appears as a large goiter in elderly female patient, for whom there is a poor prognosis
        3. Beside 67Ga this type of cancer appears to be FDG avid an noted above

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    Continue on with the Next Lecture - Thyroid Uptake and Scan

    Perchlorate Discharge Test: Not done routinely in nuclear medicine, however, it will identify Hashimoto's. Clinically the patient is usually presented with an enlarged thyroid and elevated TSH levels. The gland may be euthyroid when analyzed with an uptake procedure. However, the damage to the follicular cells effects the organification process.

    Procedure:
    1. Administer <25 μCi of 131/123I orally.
    2. Count the thyroid every 15 to 30 minutes for 1 to 2 minutes
    3. At 2 hours administer 600 to 1000 mg of KClO-4
    4. If the trapped iodine cannot be organified quickly, it is because the folliculi are damaged
    5. As a result perchlorate replaces some of the trapped iodine, % uptake drops which is an indication for Hashimoto's disease
    6. From the above procedure, which component would you correct?

    Reference

    1 - [18F]DOPA PET/ceCT in diagnosis and staging of primary medullary thyroid carcinoma prior to surgery. Rasul, S., et al.

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