notes by dr Claudio Italiano
The patient who presents the endocrinological examination with a swelling of the anterior region of the neck may be affected by a simple goiter, ie an enlargement of the thyroid gland which is not due to tumor or thyroiditis, but more simply to facts of hypertrophy, that is, the increase in volume of the organ parenchyma as a consequence of alterations of the hormonal function, that is the production of T3 and T4. (see also simple goiter).
We must understand what the role of the endocrinologist is or is not, because we have to make answers to the patient who addresses us, answers that must be as correct and precise as possible. In relating and interfacing with the patient, the physician must be extremely professional, competent and have the ability of common sense and good clinical practice, which allows us, together with the experience and knowledge, to filter the questions that the patient poses. How would you answer this question: why does a person with a goiter come to the doctor, for what symptoms? Or better: a goiter causes palpitations? No, because there is relationship between palpitations and goitre. The goiter generally accompanies euthyroidism, that is, thyroid function and the hormonal dosage are normal. So, no palpitations in the patient with goiter. Does the patient feel suffocated and present himself to the doctor? Generally this occurrence occurs in the elderly patient, who has been a goiter for some time, where the impression is made on the trachea and chondromalacia of the same trachea. Also a goiter is associated with obesity? We say that generally an hypothyroidism and goiter, can fatten, but certainly the weight is not always correlated with a goiter, also because often thyroid hormones are within the limits. It is easier for a patient with hyperthyroidism to lose weight than the opposite.
Does hypothyroidism make you fat? Not much, more than anything else it can cause fluid retention, the tissues are full of water and there is a condition of mixedema. Does goiter associate with arterial hypertension? No, of course, but it may be that a hyperthyroid may be hypertensive. Goiter is often a misunderstood condition and a patient discovers it by chance if he does an ultrasound, or rather a TSA ecocolordoppler. Another extremely frequent condition that worries the patient is the presence of laterocervical swelling. Why does the thyroid globe rise in the act of swallowing? Because it is integral with the hyoid bone, then the patient, when he swallows, perceives a mass that "rises and falls", with the deglutitive movements.On the contrary, if a doctor suspects a goiter, he implements the maneuver of swallowing and palpates the anterior region of the neck while the patient swallows: if the mass moves in solidarity with the deglutitive acts, it is just a goiter. If, on the other hand, the mass does not rise and fall, then it is not thyroid, but it could be a lymph node in most cases. The same happens when we are facing a cyst of the thyroglossian duct: it does not rise and does not go down. What if I have a lump of the pyramidal lobe? The nodules and the thyroid in this case are mobile and displaceable.
At this point we can say that the goiter is a thyroid enlargement, both of inflammatory and oncological origin. In the first case we will talk about thyroiditis in the second case of thyroid cancer. Goiter, therefore, is an asymptomatic condition in almost all cases that can only give mechanical symptoms for size, not systemic general symptoms. Simple goiter has a function associated with euthyroidism.
In general we know that in the subject with distiroidism, we can have these conditions or biochemical pattern (cf. hypo and hyperthyroidism):
- hyperthyroidism: FT4 high, TSH low or blocked, because we have so much hormone and TSH is blocked;
- hypothyroidism: FT4 Low, high TSH with the intent of stimulating a lazy thyroid to produce hormone.
Where are the values of endemic gozzo located?
Goiter, CT scan
They do not place where we would expect it but in a strange way. In fact, the FT3 is a little higher in the goiter and the FT4 is a little lower. Why? Because more FT3 is produced because there is less iodine. Since there is less iodine, the thyroid saves it by producing more the hormone that contains less iodine, ie FT3. Normally, instead, the production of FT3 at the central level, that is to say, thyroid is 20%. for FT3, while 80% is made up of T4. The T4 is then split to form T3, but this happens in the periphery with the desiodase transforming FT4 into FT3. At this point the thyroid in conditions of iodine deficiency does? Form more FT3 and less FT4.
In 70-90% of cases it is a nutritional deficiency of iodine. Functional effects are scarce, there may be mechanical effects but they are quite rare and linked to enormous goiters and euthyroidism is a condition of normality. There are molecular defects that can result in the presence of goiter in 10-15% of cases, ie in this 10-15% of cases the goiter is linked to genetic factors. It is usually sporadic and familial, associated in this case with hypothyroidism because the molecular damage involves a loss of function of the gland. Other causes of goiters are related to organ defects that have a typical family aggregation. They are related to defects of the TSH or its receptor, to defects of the iodine transporter through the genomic modification of the NIS, to the defect of action of thyroglobulin, to the reduction of thyroglobulin synthesis and to a desaturation defect of thyroglobulin when it is rescued from the thyroid lumen and hydrolysed. This molecular genetics of endemic familial goiter, you see how there can be mutations of the thyroglobulin gene, activating mutations, messenger RNA synthesis, missense mutations of the three-dimensional structure, point mutations that involve a defect or an excess of synthesis; also the TPO gene can be involved with a wide spectrum of mutations with loss of function but also the NIS with different phenotypic expressions, therefore gain or loss of function.
Let's go to what is the most common form of endemic goiter generally affects more than 10% of the population. The food factors are those known, there is a nutritional deficiency of important iodine and is the most frequent cause but also selenium and fluorine can be involved but natural substances (thiouracil), such as those present in the brassicas, may also be involved that is in the cabbages. A few decades ago in the areas of the province of Messina where many cabbages were eaten for reasons of economic poverty in isolated places in the country they only ate the produce from the garden including cabbages and broccoli containing gozzigene substances. inside the follicular cell, it is transferred into the cell, here iodine is inserted at the level of the protein matrix and poured into the lumen of the follicle. Thyoglobulin is then reabsorbed, hydrolyzed and circulated again. Iodine can only be taken by feeding. Our body can not produce iodine, we must take it with food. It represents 75% of the hormone pm therefore it has an important weight role and these are the effects of iodine deficiency, whose needs range from 1.7 mcg-3 mcg to 4-6 years, up to 150 adult mcg, and 250 mcg with pregnancy and lactation.
How does the thyroid work? We know that the thyroid is under the control of the hypothalamus-hypophyseal axis: The TRH stimulates the production of TSH which stimulates, in its turn, the production of thyroid hormone and all goes well if the essential substrate for the synthesis of the thyroid hormone, ie iodine is sufficient. If it is not enough it happens that the production of T3 and T4 is reduced, TSH increases and TSH is the most powerful factor of growth of the thyroid that causes it to grow in size and, over time, is responsible for the formation of nodules. These nodules can be cold, ie they do not work, so they do not produce hormone, or they can be hot, which are able to use iodine with a much faster, accelerated turnover that induces at the hypophyseal level the increase in hormone production so paradoxically in the deficient iodine areas there may be cases of hyperthyroidism. Nodules with functional autonomy are formed within the goiter over time. Why are nodules formed with functional autonomy? This was explained a decade ago by a Swiss who is called Spiver who has put forward a thesis that the thyroid is made up of cells that are genetically predetermined to have a control on the metabolism of iodine, with a different iodine turnover. Some cells have a very accelerated turnover and are called "hot cells", others have a very low iodine turnover and are "cold" cells and then there are cell clones that have an intermediate capacity between hot and cold ie "lukewarm" cells. As the goiter over time inevitably makes nodules and as the nodules form from the mother cells, the mother cells can be hot, cold or lukewarm. So if you form a lump from a warm cell clone, you will determine the presence of a hot nodule. The concept of "hot" nodule depends on the fact that a warm nodule at the scintigraphy appears as intensely capturing iodine, so by convention, the computer makes its hypercapacity image with yellow or red color, unlike the nodule cold that at the scintigraphy will be colored with cold colors, for ex. blue or green or black.
This is an adaptation of the gland to the nutritional deficiency of iodine, increases the uptake of iodine 127, increases the release of TSH, increases the volume of the thyroid and we will have the goiter, we have a reduction of iodine deposit, reduction of TG synthesis , reduced T4 secretion and increase of T3 production by T4, by delodination.
Today the Sicilian population ultimately consumes 50% iodized salt; on a national level we are on 60-70% so there is no more goiter. In fact, in the areas we have studied many years ago, public awareness has had appreciable results because in fact the goiter in schools has disappeared. Once there were schools, in outlying areas, where there was a goiter in 60-70% of children, a goiter clearly visible and not with ultrasound techniques, but with clinical palpation. TSH as a growth factor induces goiter growth and proliferation of nodules, which can be hot or cold and can cause cancer. That is, there can be a natural history that eventually leads to cancer. Moreover, TSH is not the only growth factor of the thyroid involved in these mechanisms, but there are also other factors whose combination may represent a stimulus to tumor growth. In order to distinguish hot and cold nodules, however, while it was once used the thyroid scintigraphy that was part of the diagnostic nodule up to 10 years ago, today ultrasound has become a sophisticated technique: comparing the ultrasound with scintigraphy, if a nodule is diagnosed, this should be studied if it is "cold" or "hot", if it is vascularized or not, evaluating the scintigraphic echoes. Next, if the nodule is suspect, e.g. greater than 1 cm, and with alterations in its context, and moreover "cold" then an agobiopsia is performed aimed at the nodule itself and histological types will be studied. Usually the cold nodule is pricked and not the hot one, since the latter is a functioning module, which overlaps the marked iodized tracer and is, therefore, ultimately a benign nodule. Making the scintigraphy, once, the endocrinologist had the possibility to avoid making the needle aspirated, discovering the hot nodule. Refining the ultrasound technique over time, this discourse failed. Let's go to the practice.
First of all there are international guidelines that must be followed. Palpable nodules are found in about 45% of adults; from the point of view of ultrasound detection, we rise to more than 50% in women and about 20% of men over the age of 50. In autopsy specimens, 60-70% are reached depending on age. This fact makes us understand that substantially the thyroid nodule is a benign pathology; the fact remains that about 5% of thyroid nodules can be malignant and very often we are faced with thyroid carcinomas which are papillary lesions with excellent prognosis; in fact there is talk of permanent remission. This happens due to the phenomenon of oncogenic activation that leads from the normal thyroid nodule to the maximum of its indifferentiation, that is to the neoplastic carcinoma, through a series of mutations that may first result in the appearance of follicular adenoma then subsequently of a follicular carcinoma and then passes for deactivation of the tumor suppressor gene p53 deters transformation of the disease. Conversely, c-ret and ras mutations may lead to papillary thyroid carcinoma formation and in this case, due to inactivation of p53, can lead to disease. In 20% of cases the mechanism is not responsible for hot thyroid nodules. The hot nodule can also originate from a mutation of the TSR receptor. In fact the point mutations that activate the TSR receptor are responsible for 20% of the hot nodules. This thyroid tumorigenesis follows the same principle of the colon cancer model, in which it passes from a normal cell that has the maximum of differentiation, which works, to an undifferentiated cell. If we have a benign thyroid nodule, today the guidelines tell us that if we have twice a thyroid nodule and the cytologies are normal, we only have to monitor the hormones. Over the period from 73 to 2002, there has been an increase in the incidence of tumors in the United States, but only in the papillaries, follicular ones have remained the same. While in the graph to the right it says that in the papillary tumors small tumors have increased. So we are talking about an increase in small papillary tumors but because we have refined the diagnostic techniques. That is, there are no new tumors, we simply find more because the diagnostics have improved. In reality it is only partially true, that is, the incidence of small papillary tumors has increased not only because they are found more for the best diagnostic capacity but also
because they have increased in number. Another '94 historical work on thyroid neoplasms says that if the tumors are later treated, the greater the chance of dying of cancer. So this means that we must commit ourselves to doing the right job at the right time. This is a work that compares the various guidelines between them, written by various associations. It's a job that brought 152 guidelines but in the end only 10 of these were reliable. There is a general agreement between our work-up agreements, that is, a general agreement on the diagnostic work-up that is done. When a patient arrives with a lump we go to see to the inspection if the nodule is evident (in the sense that the mass is seen), otherwise we proceed with the palpation, following margins, consistency, form. But the first thing we need to focus on is the history, to understand if the patient comes from an endemic area, if he takes iodine, if he is familiar with thyroid cancer, if he has lost weight (there is weight loss in both hyperthyroidism and in the tumor but in reality in the case of the tumor the weight loss is late, not sudden). In 1986 a nuclear reactor exploded in Chernobyl and thyroid cancer increased in children 100 times, so the other cancer makers are ionizing radiation.