The thyroid in these lesions is often part of a multi-tissue proliferation, that is tissues from all three embryological germ layers are represented. In most cases the thyroid either appears normal or shows changes consistent with colloid goiter. In rare instances, the thyroid will appear hyperplastic or even show lymphocytic infiltration mimicking thyroiditis. Rarely neoplasms originating in the thyroid gland including papillary carcinoma, follicular carcinoma or even poorly differentiated carcinoma can arise in a background of struma ovarii.
Unusual situations have been described wherein the struma ovarii or tumors therein may hyper secrete thyroid hormone and lead to clinical hyperthyroidism 56 — The most common histology is that of hepatocellular carcinoma.
The tumor produces these stimulatory hormones and when tumor is entirely removed the levels of hormones drop and hyperthyroidism regresses 59 , Gestational trophoblastic disease including hydatidiform mole and choriocarcinoma is associated with marked elevation of beta human chorionic gonadotropin beta HCG.
Although it is rare to see tissue from the thyroid in these patients, it is expected that the gland would show a hyperplastic appearance with papillae and cellular enlargement. Lymphocytic infiltration would be absent. Treatment of the gestational trophoblastic disease by uterine evacuation followed by chemotherapy usually leads to resolution of the hyperthyroid state 61 — A variety of classes of pharmaceutical agents can cause thyroid dysfunction.
It is beyond the purpose of this review to engage in a lengthy discussion of the clinical disorders caused by these drugs.
Some of these interfere with metabolism of iodine, others with the production of thyroid hormone and its conversion to active moieties, and still others do not produce abnormalities in thyroid function but cause chemical interference with thyroid function test measurements. Many drugs can affect thyroid function phenytoin and derivatives, therapies associated with interleukin administration usually in oncology settings 65 — The pathologic counterparts for these include lymphocytic infiltration of the gland with or without fibrosis Those drugs that cause hyperthyroidism are fewer and they usually exert their effect through interference with the metabolism of iodine.
It is rare to see pathological specimens from these patients; the exceptions is the cardiac drug, amiodarone, interleukin containing regimens for chemotherapy and most recently PDL 1 or immune checkpoint inhibitors; these will be discussed below. The literature notes that there are two types of thyroid lesions that are associated with amiodarone, an iodine containing compound used to treat cardiac arrhythmias.
Amiodarone induced thyrotoxicosis AIT is classified as type I and type II, the former occurs in patients with underlying thyroid disease such as nodular goiter, autonomous nodular goiter or Graves' disease, whereas, Type II is caused by iodine-led destruction of the thyroid follicular epithelium in a normal thyroid gland.
Because amiodarone is vital to control the cardiac problems, it is often not possible to wean the patient from the medication or to change to another drug. Thyroid excision is undertaken in patients who do not respond to medical therapy in order to treat the hyperthyroidism which often worsens cardiac symptoms 69 — If the gland is already pathologically abnormal nodular thyroid goiter, Graves' disease , the pathology of the resected gland shows follicular disruption with histiocytes infiltrating the follicular epithelium and colloid Figures 5 , 6.
Rarely, inflammatory cells are noted within the thyroid parenchyma Type I. On the other hand if the thyroid is histologically normal Type II , the pathologic lesions show much milder follicular damage 73 — These changes are similar to those seen in amiodarone induced pulmonary and liver toxicity 76 , Ultrastructural studies of both lung and thyroid tissues have shown lysosomal and mitochondrial inclusions in follicular cells consistent with follicle cell destruction However, this simple explanation is not the only reason for the thyroid dysfunction.
For example, co-cultures of amiodarone with human thyrocytes have shown the production of interleukin 6 and the drug also decreases the sodium-iodide symporter mRNA in the follicular cells Figure 5. Amiodarone associated follicular cell damage.
Low and high power showing large thyroid follicles filled with colloid and numerous histiocytes arrow heads, 3A,B. The removal of the thyroid in amiodarone induced hyperthyroidism results in resolution of the hyperfunction and reversion of the cardiac disorder to baseline 75 , In rare instances, interferon-alpha treatment can lead to classic Graves' disease and even Graves' opthalmopathy; and these condition can persist even after the cessation of therapy 67 , At present, several tyrosine kinase inhibitors TK1 are being used to treat different types of malignant neoplasms.
TKI can lead to various forms of toxicities including those related to endocrine organs. Transient hyperthyroidism can occur during TKI therapy and is often due to destructive thyroiditis 67 , Immune check-point inhibitors with their antitumor activity have shown to improve the survival rates of non-small cell lung carcinoma, melanoma, bladder and renal carcinoma, and ovarian carcinoma.
The term mechanico-destructive hyperthyroidism non-hyperthyroid thyrotoxicosis has been coined by us to describe those conditions in which relatively rapid destruction of thyroid tissue followed by release of stored thyroid hormone from colloid as follicles or destroyed produces hyperfunction.
Both benign and malignant conditions can be associated with this type of hyperthyroidism. This reflects the destruction of the thyroid gland by the inflammatory or neoplastic process; the follicular epithelium is destroyed and cannot take up the radioactive isotope.
This condition is believed to be associated with systemic and or thyroid infection usually viral in nature, is often a painful cause of hyperthyroidism. Patients with this disorder will often present with neck pain which may be referred to the jaw or the chest. In the initial phases of this disease symptoms of hyperthyroidism are often clinically evident.
As the gland is replaced by the inflammatory granulomatous process, the follicular epithelium is destroyed, follicles of ruptured and stored thyroid hormone within the colloid is released into the circulation. Unlike usual Graves' disease however the thyroid cannot take up iodide and produce more hormone. Thus, a phase of hypothyroidism is noted until healing occurs 82 — Malignant neoplasms which are rapidly growing can be associated with this mechanic-destructive type of hyperthyroidism.
The tumors most often identified are anaplastic thyroid carcinoma, malignant lymphoma usually primary in the thyroid and of large cell type and poorly differentiated metastatic cancers involving the thyroid breast carcinoma and lung carcinoma most commonly.
Histologically one sees the highly malignant tumor freely infiltrating the thyroid, destroying and replacing the tissue, with rupture of the follicles and release of thyroid hormone containing colloid. The rapidity of the process can lead to market elevation of thyroid hormone and a toxic state simulating thyroid storm 85 — In affected patients, there is often near complete destruction of the gland and the eventual development of hypothyroidism.
Patients need to be supplemented with thyroid hormone to maintain a euthyroid metabolic state; if treatment of the tumor is successful, regeneration of thyroid follicles may occur from the residual thyroid tissue and as in subacute thyroiditis, normalization of thyroid function may occur 86 — This review has described the pathology and clinicopathologic correlations of unusual lesions of the thyroid and extrathyroidal tissues which can show clinical manifestations of hyperthyroidism.
Although most of these conditions are rare especially when compared to Graves' disease or toxic nodular goiter, it is important for both the clinician and pathologist to be aware of them as diagnostic considerations. VL and ZB have equally contributed to the literature review, drafting the manuscript and obtaining microscopic photographs.
Both authors have reviewed the final version of this manuscript before submitting it to topic editors of the journal. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Thyroid nodules in Graves' disease:classification, characterization, and response to treatment. Thyroid —6.
Gossage A, Munro D. The pathogenesis of Graves' disease. Clin Endocrinol Metab. Burman K, Baker J. Immune Mechanisms in Graves' disease. Endocr Rev. Karoutsou E, Polymeris A. Pathogenesis of Graves' disease focusing on Graves' ophthalmopathy. Endocr Regul. The common incidence of Basedow's-Graves' disease and chronic lymphocytic thyroiditis.
The edition of Hirsch's classic pathology text states that even though goiter and cretinism have to be reckoned among the infective diseases, iodine treatment is still recommended for this condition. He boiled the thyroid glands of sheep in dilute sulfuric acid and then collected the flocculent precipitate that was deposited. While examining this precipitate, he noticed a high level of iodine present in it. It was used to treat patients with goiter and showed successful results.
Many surgeons of the 19 th century also attempted unsuccessfully to treat thyroid disease. These included Curling in , Gull in , and Ord in , Fagge had described the difference between sporadic and endemic cretinism.
Public health and thyoidology also blended together in the 19 th century. In , Boussingault suggested salt iodization to prevent goiter. Chatin proved in that fresh water aquatic plant derived iodine could prevent endemic goiter and cretinism.
He correlated these conditions with iodine deficiency, and recommended iodine supplementation in drinking water, using mineral water springs. However, it was nearly years later that his vision was realized and iodine-rich salt was made commercially available.
Although this idea was scientifically correct, it was rejected by French authorities. The first public health experiment in thyroidology was also carried out in this century, using potassium iodine in salt, as solution, or as tablets.
However, because of side effects due to the high doses used, iodine prophylaxis was abandoned. Much work was done on excessive function of the thyroid gland as well. The Irishman Robert James Graves , described many patients with exophthalmos and goiter. David Marine , also known as the Nestor of Thyroidology,[ 23 ] proved that iodine is necessary for thyroid function in Four years later, he treated Graves disease with iodine. In , he introduced goiter prevention with iodine, using a low dose of parts of iodine.
In , he described cyanide goitre due to thiocyanates found in plants of the genus Braissicaceae cabbage, cauliflower, turnip. In , Brown-Sequard suggested the use of testicular extract for the rejuvenation of elderly men. The first persons to use thyroid extract were Horsley and Murray. Many skeptics voiced concern at the use of sheep's thyroid.
A senior member of the Royal Society of Medicine said it would be just as sensible to treat a case of locomotor ataxia with an emulsion of spinal cord. Thyroid preparations were administered orally and as injectables by various workers. Thyroid extract soon became an accepted part of current medical practice.
Adolf Oswald was able to identify thyroid colloid protein as thyreoglob. It took 3 tons of porcine thyroids to obtain 33 g of pure thyroxine. Synthetic thyroxine was made by Harigton and Barger in Trirodothyroxine was discovered much later in by gross and Pitt—Rivers.
A major advance in thyroidology occurred in , when Roitt, Doniach, Campbell and Hudson demonstrated autoantibodies in Hashimoto's disease. Along with developments in diagnosis, clinical thyroidology also grew in the 20 th century, Charles Mayo first used the term hyperthyroidism in , and in the same year, Brissaud described thyroid infantilism. Iodine therapy was used in by Marine for Graves disease, and in preoperative management of exophthalmic goiter in by Plummer and Boothby.
Radioactive iodine was used in Graves disease, independently, in , by Hertz and Roberts, as well us Leblond. Medical management did not lag behind. In , Astwood used thiourea and thiouracil in Graves disease. In , the synthess of methimazole by Jones, Kornfeld, Mc Laughlin and Anderson was witnessed, while was the year when Lawson, Rimington and Searle synthesized carbimazole, Commercial synthesis of levothyroxine was successful on Edward Kendall started working on isolating the pure form of thyroxine in By paying careful attention to the hydrolysis of the gland, he was able to isolate thyroxine in a pure form in Charles Harrington prepared synthetically a compound by condensation of two molecules of diiodotyrosine in This led to the discovery of the exact structure of thyroxine.
He had innovated many techniques in hernia, osteomychtis, dislocalocations, use of silk sutures, asepsis and thyroid surgery. Till date, he remains the only winner of the Noble Prize for work done in thyroidology G. In , Jack Gross and Rosalind Pittrivers detected the presence of a more potent thyroid hormone while carrying out researches on mice fed with radioactive iodine. Even though the scientists credited with the discovery of the thyroid gland and its diseases are mostly from the 19 th or 20 th century, the contributions of the earlier scientists should not be disregarded.
The interests of people in the thyroid gland have always been immense because of the widespread prevalence of its diseases. Therefore the earliest references to the gland date back to 1 st century AD. The Chinese, Egyptian, Indian, Greek and Byzantine medicines are especially rich in their knowledge on the subject. Source of Support: Nil,. Conflict of Interest: None declared. National Center for Biotechnology Information , U. Indian J Endocrinol Metab. Author information Copyright and License information Disclaimer.
Shifa College of Medicine, Islamabad, Pakistan. Corresponding Author: Mr. E-mail: moc. This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-Share Alike 3. This article has been cited by other articles in PMC. Subtypes indicate whether hyper-, hypo- or euthyroidism is present. Until recently hypothyroidism was worldwide most often caused by iodine deficiency [ 49 ]. Considering the many programs initiated where food supplies are fortified with iodine, today autoimmune thyroid disease might and certainly ought to be the most frequent cause of hypothyroidism.
Recent reviews have summarized the various causes of congenital and acquired hypothyroidism [ 50 , 51 ]. Mixed or intermediate forms are encountered. The distribution of the forms varies according to the endemic area. Obviously, iodine deficiency is a key factor in both types. Whereas the myxedematous type as the name implies is clinically associated with hypothyroidism including stunted growth and sexual immaturity , patients with the neurological type are often euthyroid though frequently with goiter.
Iodine given before or early in the pregnancy will prevent the development of neurological cretinism [ 53 ]. In an important study [ 54 ] from Congo, Vanderpas and coworkers showed that in the myxedematous type of cretinism treatment with iodine will normalize thyroid function—provided treatment is begun early in the postnatal period.
If not, the prognosis remains dismal. It has puzzled researches how iodide deficiency of similar magnitude may lead to such clinical diversity. In a careful and well-argued analysis of published data and their own recent findings, Boyages and Halpern have suggested that two events are involved in endemic cretinism [ 55 ]. One is a transient thyroxine deficit transmitted from mother to fetus around the time of the midtrimester with neurological and intellectual consequences.
This event occurs in all cretins whereas the second postnatal period of thyroid hormone deficit takes place in a subgroup only. It is the length and severity of this second event that will decide the extent of clinical hypothyroid symptoms present.
Though the exact cause of myxedematous cretinism is still unclear, a wealth of skillful research has demonstrated the importance of iodine. Zimmermann has recently published a superb review of the early iodine prophylaxis [ 56 ]. In a detailed report pages delivered in by a committee set up by the Clinical Society in London on the relationship between cretinism, myxedema, and struma thyropriva, the clinical symptoms are described in detail but treatment is hardly mentioned [ 57 ].
However, a few other investigators were toiling with the possibility of therapy and clarifying thyroid function. Thus, the eminent German physician and physiologist Moritz Schiff — while working in Berne performed important experiments. Similar grafting was performed by von Eiselberg who at the same time transplanted thyroid and parathyroid tissue and thus became the first to perform parathyroid grafting [ 59 ], though obviously he was unaware of the function of parathyroid glands.
They were discovered in [ 5 ], but it would last almost until the end of the century before their function was recognized [ 60 ]. Thyroid transplantation in man was soon taken up by Bettencourt and Serrano in Lisbon [ 61 ].
The effect was remarkably swift and—in fact, so swift that the authors wisely suggested that it might be due to the absorption of the juice from healthy thyroid gland by the tissues of the patient. In a letter in June [ 62 ], Horsley informed George Redmayne Murray — about the progress made in various European countries as to finding treatment for hypothyroidism. Murray at that time was a pathologist at the Hospital for Sick Children in Newcastle. A few months later, Murray published the first account of a human patient with hypothyroidism given substitution with thyroid extract injected subcutaneously [ 63 ].
Clinically, the effect was beyond doubt. The patient lived almost 30 years on thyroid substitution—eventually to die of cardiac failure in [ 64 ]. Within months, it was discovered that oral administration of thyroid extract was effective [ 65 — 67 ]. Fenwick [ 68 ] noted a marked increase in diuresis after commencement of thyroid substitution therapy. Naturally, the central question as far as thyroid extract was concerned, was which substance was responsible.
Magnus-Levy demonstrated the important fact that desiccated thyroid and iodothyrin increase oxygen consumption and output of carbon dioxide [ 70 ]. A vivid description has been given of what a physician might encounter at that time [ 71 ]. Around , an Irish general practitioner was asked to see a lady who obviously was dying, her family being aware no treatment was possible.
The diagnosis was clinically obvious. The GP had just read in the British Medical Journal about the proposed treatment of myxedema and straight away got hold of thyroid glands from sheep. Following the instructions in the papers, he prepared a substance which was administered to the patient who stunned everybody by a swift and complete, almost biblical, recovery. Incidentally, the physician later gained further fame by operating on an old and destitute woman on his kitchen table, curing her cataract.
In , Murray—not without a little pride—summed up the present state of treatment of hypothyroidism [ 72 ]. In the idiopathic form it is a symptom of chronic interstitial thyroiditis, just as anasarca may be a symptom of renal disease or ascites of hepatic disease. Thus the myxedema can be cured, although the chronic interstitial thyroiditis still remains.
In on Christmas day, at the Mayo Clinic, Edward Calvin Kendall — crystallized a substance—later to be named thyroxine—containing When he repeated the procedure, he failed to isolate any crystals. It would take 15 frustrating months finally to get the procedure right. This allowed studies on its physiological properties.
Perhaps because of the war, thyroxine was not chemically identified until [ 75 ]. About 25 years later, Gross and Pitt-Rivers [ 76 ] detected the second thyroid hormone—triiodothyronine, which at the same time also was demonstrated by French investigators [ 77 , 78 ]. Almost as if they were introducing a completely new drug, Hart and Maclagan in [ 79 ] reviewed the use of thyroxine and particularly L-thyroxine.
Actually, it had been available since the s but had not gained wide acceptance maybe because of its high cost —despite its obvious advantages. Desiccated thyroid was much used for many years and as late as leading British endocrinologists felt compelled to warn against its use [ 80 ].
It is still being marketed and hence probably used in some countries—for example, USA. He had advocated the use of extracts from ovaries and testes—many of his theses were based on excellent results in experiments he had performed on himself [ 82 , 83 ].
In some respects, his theories would lead medicine into an abyss of eeriness and utter bewilderment, but in other instances it would precipitate important progress in endocrine therapy. There can be little doubt that the benefit of thyroid substitution was a major support for the soundness of organotherapy.
A veritable industry grew up and extracts from a variety of organs including brain and spinal cord were marketed and widely used Figures 3 a — 3 c.
Organotherapy could claim some other successes. Around Vassale in Italy [ 84 ] and Gley [ 85 ] in France had injected thyroidectomized dogs with extract of thyroid glands from sheep.
There was an excellent effect on postoperative tetany which they ascribed to thyroid insufficiency. In , two reports, one from Germany [ 87 ] and one from Italy [ 88 ], demonstrated the swift and unquestionable effect of extract of the posterior lobe of the hypophysis on polyuria in diabetes insipidus. Patients were made devour a whole pancreatic gland per day.
The results, however, were dismal. Pancreatic transplantation was attempted, first in [ 90 ], but proved an utter disaster. As an illustration of the belief in organotherapy though not necessarily involving the thyroid , an interesting piece of evidence is provided by a short novel The Creeping Man [ 91 ] written by Sir Conan Doyle — —a physician by education.
Briefly, the story deals with a professor who at a somewhat advanced age plans to marry a much younger and pretty woman. To some consternation of his family members and associates, his behavior undergoes a distinct change. Thyroid hormones help the body use energy, stay warm and keep the brain, heart, muscles, and other organs working appropriately. The immune system destroys foreign invaders with substances called antibodies produced by blood cells known as lymphocytes.
Sometimes the immune system can be tricked into making antibodies that cross-react with proteins on our own cells. In many cases these antibodies can cause destruction of those cells. This results in an overactive thyroid hyperthyroidism. The diagnosis of hyperthyroidism is made on the basis of your symptoms and findings during a physical exam and it is confirmed by laboratory tests that measure the amount of thyroid hormones thyroxine, or T4, and triiodothyronine, or T3 and thyroid-stimulating hormone TSH in your blood see the Hyperthyroidism brochure.
The choice of initial diagnostic testing depends on cost, availability and local expertise. Also, in some patients, measurement of thyroidal blood flow with ultrasonography may be useful to establish the diagnosis if the above tests are not readily available. The treatment of hyperthyroidism is described in detail in the Hyperthyroidism brochure.
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