Thyroid: why is it not functioning?

Hypothyroidism is a common endocrine disorder resulting from deficiency of thyroid hormone. It usually is a primary process in which the thyroid gland is unable to produce sufficient amounts of thyroid hormone.

Hypothyroidism can also be secondary—that is, the thyroid gland itself is normal, but it receives insufficient stimulation because of low secretion of thyrotropin (ie, thyroid-stimulating hormone [TSH]) from the pituitary gland. In tertiary hypothyroidism, inadequate secretion of thyrotropin-releasing hormone (TRH) from the hypothalamus leads to insufficient release of TSH, which in turn causes inadequate thyroid stimulation.

Hypothyroidism can be caused by caused by drugs.

A recreational 22 year drug abuser who had been treated for his addiction twice was found by the police on the roadside in a slum area. He was in an advanced state of malnutrition, had a productive cough. After his second relapse into addiction his family had abandoned him and he lived by begging and petty theft. He ate at soup kitchens sometimes, but often just found leftovers in the trash. In the hospital he was found to have advanced pulmonary tuberculosis with multiple cavities in both lungs. Multi drug resistant TB was suspected based on his lifestyle. This was later confirmed on culture of the sputum by the Bactec system. He was started on rifampicin, isoniazid, ethambutol, ethionamide, ciprofloxacin and azithromycin. He was kept in the hospital and his nutritional status was improved with a balanced diet, food supplements and vitamin supplements. Drug and alcohol withdrawal were monitored and after 4 weeks he was sent over to a charitable organisation which ensured a bed to sleep in, three meals a day, social interaction and supervised oral therapy for tuberculosis. On review after 6 weeks it was noted that he was apathetic, tired  and drowsy most of the time. He had gained weight but his appetite was poor. He did not have jaundice or signs of liver disease. His feet were swollen but the swelling did not pit on pressure. He was still coughing but did not have hemoptysis. His psychiatrist assessed him and diagnosed him to be in the depressive stage of bipolar disorder and started him on lithium after monitoring his creatinine clearance. His pulse was persistently between 45-60 beats per minute and he was severely constipated and needed enemas to empty the bowel. His thyroid was not enlarged but his TSH was above the range of the laboratory. Third-generation TSH assays are readily available and are generally the most sensitive screening tool for primary hypothyroidism. The generally accepted reference range for normal serum TSH is 0.40-4.2 mIU/L. Urinary iodine measurement was not available in the laboratory.

What is causing his hypothyroidism?

Low dietary intake is the commonest cause. In areas of adequate iodine intake, autoimmune thyroid disease (Hashimoto disease) is the most common cause. Hypothyroidism may also be drug-induced or otherwise iatrogenic.

Is it dietary deficiency?

  • Worldwide, iodine deficiency remains the foremost cause of hypothyroidism. Iodine is an essential component of thyroxine (T4) and triiodothyronine (T3), and it must be provided in the diet.  The Iodine Global Network maintains a website with databases of information about iodine nutrition in different countries and an information reference desk. Iodine deficiency is rare in adults without a goitre or a reason for malabsorption.
  • How much iodine do we need daily? The thyroid gland needs 52 mcg daily to synthesize adequate amounts of T4. Severe iodine deficiency develops when iodide intake is chronically <20 mcg/day.
  • Where can we find iodine in our diet? Fish, seafood, kelp, some drinking water, and vegetables grown in iodine-sufficient soil usually near the sea or diet to which iodised table salt is added. Cow’s milk is a source of iodine owing to iodine in cattle feed and the use of iodophor udder cleansers in the dairy industry. Sea salt naturally contains only a small amount of iodine. Advise people specially if there are young children or women of childbearing age in the family to buy iodine enhanced table salt.
    • The World Health Organization (WHO) recommends: 90 mcg of iodine daily for infants and children up to 5 years; 120 mcg for children 6 to 12 years; 150 mcg daily for children ≥12 years and adults; 250 mcg daily during pregnancy and lactation.
    • Iodine deficiency can be assessed by measuring the urinary iodine excretion. Mild iodine deficiency is defined as a median urinary iodine concentration of 50 to 99 mcg/L, moderate deficiency as 20 to 49 mcg/L, and severe deficiency as <20 mcg/L.
  • How can you administer iodine to a person?
    • Iodised salt is the simplest way and is used for prophylaxis.
    • Lipiodol, developed as a radiographic contrast agent, contains 480 mg iodine/mL. A single oral dose of 0.5 to 1 mL provides an adequate amount of iodine for six months to one year; intramuscular administration of the same dose provides an adequate amount for two to three years.
    • If the patient is hypothyroid or has a puberty goitre use levothyroxine for the treatment of hypothyroidism. No iodine is needed.
  • Is this patient’s hypothyroidism drug induced? Which drugs can cause hypothyroidism.
    • Iodine. Upon exposure to high concentrations of iodide, thyroid cells decrease the oxidation of iodide and thyroid hormone formation (the Wolff-Chaikoff effect). The Wolff-Chaikoff effect is short-lived because the sodium-iodide symporter is capable of rapidly downregulation. However, exposure to excess iodine can produce more profound and sustained hypothyroidism in individuals with abnormal thyroid glands (eg, from autoimmune thyroiditis, subtotal thyroidectomy, or prior radioiodine therapy).  Iodine solutions, such as saturated solutions of potassium iodide (SSKI) or potassium iodide-iodine (Lugol’s solution) were used for the treatment of endemic goitre, are now considered dangerous. They have a minor role in the treatment of thyroid storm and preparing patients for thyroidectomy in hyperthyroidism. This patient has not been given iodine as yet.
    • Lithium. Can cause an enlargement of the thyroid and the production of antithyroid antibodies. Appropriate treatment is the administration of T4, not cessation of lithium therapy
    • Rifampicin and others. Phenobarbital, rifampin, phenytoin, and carbamazepine increase the metabolism of T4 and T3. As a result, T4-treated hypothyroid patients may need a higher dose when treated with any of these drugs. Conversely, the doses of these drugs may need adjustment because their metabolism varies according to thyroid status.
    • Ethionamide.
    • Amiodarone may cause hypothyroidism or hyperthyroidism by different mechanisms in susceptible patients. It inhibits T4 conversion to T3. As a result, patients treated with amiodarone who do not develop hypothyroidism or hyperthyroidism often have low serum T3 concentrations, while serum total and free T4 concentrations are raised to just above the upper limit of the normal range.
    • Tyrosine kinase inhibitors — Oral tyrosine kinase inhibitors (eg, sunitinib, sorafenib, imatinib, motesanib) used for the treatment of gastrointestinal stromal tumors, renal cell carcinoma, hepatocellular cancer, chronic myeloid leukemia, and in other cancers can cause hypothyroidism.
    • Aminoglutethimide — Aminoglutethimide, which is used to reduce adrenal secretion in patients with Cushing’s disease and adrenal, breast, or prostatic cancer, can cause hypothyroidism.
    • Interferon alfa and interleukin-2 — Interferon alfa and interleukin-2 can cause both permanent and transient hypothyroidism by inducing antibodies.
    • Sulfonamides and sulfonylureas, have been implicated as causes of hypothyroidism in occasional patients.
    • Drugs that influence thyroid hormone binding in serum. This does not affect free T4 levels. 
      • Among those that raise serum TBG, the most important are estrogen or selective estrogen receptor modulators (SERMs, including oral contraceptives, tamoxifen, and raloxifene), methadone, and fluorouracil. Thyroid hormone doses may need to be adjusted in hypothyroid women who initiate estrogen replacement therapy.
      • Of those that lower serum TBG, the most important are androgens, anabolic steroids, and glucocorticoids.
      • Several other drugs (such as salicylates, salsalate, fenclofenac and mefenamic acid, and furosemide) lower serum T4 and T3 concentrations by blocking hormone binding to TBG

Some drugs may affect TSH secretion. Those that inhibit TSH secretion are:

  • Pharmacologic doses of glucocorticoids (more than 20 mg per day of prednisone or its equivalent)
  • Dobutamine in high doses.
  • Dopamine (more than 1 mcg/kg per minute)
  • The somatostatin analogue octreotide (more than 100 mcg/day) 
  • Bexarotene, a retinoid X receptor ligand an antineoplastic drug used in cutaneous T cell lymphoma, Mycosis fungoides/Sezary syndrome.
  • Metformin can cause suppression of TSH.

Interpreting the TSH levels requires some thought.

  • If the serum TSH assay in use has a sensitivity in the range of 0.05 to 0.1 mcU/mL (mU/L), the administration of these may result in an “undetectable” serum TSH concentration, similar to that in patients with hyperthyroidism.
  • If a more sensitive assay that detects 0.01 mcU/mL is used, the serum TSH values in patients being given these drugs are usually in the range of 0.08 to 0.4 mcU/mL. These values can easily be distinguished from the suppressed values in patients with hyperthyroidism (<0.01 mcU/mL).

What are the consequences of iodine deficiency?

Diffuse and nodular goiter — Goiter is the most obvious manifestation of iodine deficiency. Low iodine intake leads to reduced T4 and T3 production, which results in increased thyroid-stimulating hormone (TSH) secretion in an attempt to restore T4 and T3 production to normal. TSH also stimulates thyroid growth; thus, goiter occurs as part of the compensatory response to iodine deficiency. When drugs affect the thyroid gland and cause hypothyroidism a goiter does not develop.

Is an iodine-deficiency goitre harmless?  

Long thought to be only a cosmetic nuisance the goitre undergoes change. The goitre is initially diffuse in children and adolescents but eventually becomes nodular because the cells in some thyroid follicles proliferate more than others, and over time, nodules can enlarge and undergo cystic degeneration, hemorrhage, and calcification. Adults who lived in conditions of longstanding iodine deficiency have nodular goiter. In longstanding goitres cells can mutate and a state of TSH independence can occur and cause hyperthyroidism. In regions of mild to moderate iodine deficiency, toxic multinodular goiter is a common cause of hyperthyroidism in older adults.

Use the ultrasound of the neck to assess the thyroid. You will get a better idea as to its volume.

Thyroid Cancer and iodine deficiency.

Correction of iodine deficiency in many countries has shown an increase in papillary thyroid cancer over anaplastic and follicular thyroid cancer. Thus, by reducing these more aggressive subtypes of thyroid cancer, iodine prophylaxis programs may be contributing to the decrease in thyroid cancer mortality

Hypothyroidism. Hypothyroidism due to very low iodine intake is now extremely rare. Adults have the typical clinical manifestations of hypothyroidism and usually a goiter.

Hypothyroidism in pregnancy.

For the first 12 weeks of gestation, the fetus is completely dependent upon maternal T4. During the 10th to 12th week of gestation, fetal TSH appears, and the fetal thyroid is capable of concentrating iodine and synthesizing iodothyronines. However, little hormone synthesis occurs until the 18th to 20th week. Hypothyroidism during these critical periods of development and that which continues after the fetal thyroid develops in the setting of ongoing maternal iodine deficiency leads to permanent intellectual disability, which, in its most severe form, is known as cretinism.

Iodine deficiency in pregnancy is treated with thyroxine in sufficient dosage to maintain TSH in the trimester specific range.

In hypothyroidism the patient’s presentation may vary from being asymptomatic to myxedema with multisystem organ failure. Because nearly all metabolically active cells require thyroid hormone, deficiency of the hormone has a wide range of effects. Classic signs and symptoms, such as cold intolerance, puffiness, decreased sweating, and coarse skin, may not be present, especially in younger patients.

First check the TSH level. If TSH levels are above the reference range and you suspect hypothyroidism, the next step would be to measure free thyroxine (T4). Subclinical hypothyroidism, also referred to as mild hypothyroidism, is defined as normal serum levels of free T4 and triiodothyronine (T3) with a slightly high serum TSH concentration.

For hypothyroidism, thyroid hormone is administered to supplement or replace endogenous production. In general, hypothyroidism can be adequately treated with a constant daily dose of levothyroxine (LT4). The treatment is lifelong but must be monitored as the condition may be transient.

 

 

Published by

shaheenmoin

I am a Professor of Medicine and a Nephrologist. Having served in the Army Medical College, Pakistan Army for 27 years I eventually became the Dean and Principal of the Bahria University Medical and Dental College Karachi from where I retired in 2016. My passion is teaching and mentoring young doctors. I am associated with the College of Physicians and Surgeons Pakistan as a Fellow and an examiner. I find that many young doctors make mistakes because they do not understand how they should answer questions; basically they do not understand why a question is being asked. My aim is to help them process the information they acquire as part of their education to answer questions, pass examinations and to best take care of patients without supervision of a consultant. Read my blog, interact and ask questions so that I can help you more.

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