I remember four sisters of Messina, who suffered from hypothyroidism; three had remained young ladies and had never raised their sails when the wind of life had blown. So you saw them in the house, torpid, with porcine eyes, hands clumsy, obese, always sitting on chairs, prague, sit in old salons half musty, with the Persians closed from which they peeked the way, the voice heavy, hoarse, croaking , the slow thought, which we constantly called shouting disconnected phrases, always covered with sweaters and sweaters, the crocheted wool cape on the round shoulders and gibbose, always closed in the bathroom for constipation, prominent lips and tongue that protruded from the mouth with a semi-open lower lip, like a drawer. One of the sisters, the greatest, however, of a very lively intelligence, elegant, cultured, had refused prestigious positions, having graduated, and dedicated her life to the family, represented by the sick sisters ...
It is essentially a deficit of the thyroid hormones that do not, however, at
the level of the target tissues, their hormonal action; it is clear that the
causes that determine hypothyroidism are multiple however based on the cause
of hypothyroidism, we can recognize different forms.
Basically we recognize
three:
1. primary hypothyroidism: more frequent form; when the cause of hypothyroidism
is linked to a primitive intrinsic problem of the thyroid gland which for this
reason does not work.
2. central hypothyroidism, which can be subdivided into two subgroups: a)
secondary hypothyroidism when the cause is a defect of secretion of TSH,
therefore a hypophyseal problem; b) tertiary hypothyroidism, when the defect is
in the secretion of the TRH, then linked to pathologies of the superior organ of
control, the hypothalamus.
3. peripheral hypothyroidism: to refer to a defect of peripheral action of the
thyroid hormones, both for a receptor problem, and for a problem of the
intracellular carriers of the thyroid hormones, because the thyroid hormonal
action is carried out, in turn, for a interaction of the hormone itself with a
kind of second hormone located at the nuclear level, so the assumption for which
the thyroid hormone acts is that it must nevertheless enter the cell inside, and
finally for problems on the peripheral metabolism of the hormones thyroid, for
example problems with desiodases, which are those enzymes that convert T4, which
is the inactive hormone in T3, which is the active hormone.
When the thyroid gland does not work, this is called a condition of primary hypothyroidism. It can depend on:
- Autoimmune thyroiditis, generally it is chronic thyroiditis on an autoimmune basis, see the link.
- Forms of reversible immune hypothyroidism, such as a very frequent form is postpartum thyroiditis;
- Post-surgical hypothyroidism, after total thyroidectomy, where obviously there is the removal of the thyroid gland and sometimes also of the parathyroid glands,
with calcium deficiency available in the circulation and serious problems of calcium-reduced tetany.
- Metabolic radiotherapy of the thyroid, for example in the case of treatment of functioning adenomas.
- External irradiation of the neck, as is done in the radiant treatment of lymphomas of the mediastinal region or of the head-neck region.
- Infiltrial or infectious thyroid problems (thyroiditis causes)
- Thyroid dysgenesis, congenital defects of thyroid gland synthesis, these genesis defects can be fundamentally grouped into thyroid hypoplasia, that is
when there is the absence of a lobe or isthmus or in total thyroid agenesis, that is when there is a gland not fully developed, so there is no thyroid gland.
Instead, we are talking about thyroid ectopia when the thyroid gland is not located in a normal site, ie it can be located between the second and fourth
tracheal cartilage, for example a lingual, sublingual thyroid, there are mediastinal thyroids and so on.
- Primary hypothyroidism linked to a defect of secretion of the thyroid hormones: this can be determined in the ectopic thyroid forms in which the gland does not
work completely due to problems of dysgenesis, with a lack of function of the follicular tissue itself.
-Hypothyroidism due to problems of secretion of hormones linked or to an iodine deficiency or to an excess of iodine. Iodine,
it is the fundamental constituent of thyroid hormones. If there is little iodine, the gland synthesizes a few hormones. Or by excess, if there is too much iodine,
there is a blockage of the NIS (sodium / iodide symporter), the so-called Wolff-Chaikoff effect, so there is a down regulation of the NIS, the thyroid to
protect itself from excess iodine does not take it anymore. It is what paradoxically happened after the Chernobyl nuclear fallout, when to protect the
population they gave themselves iodine tablets to block the thyroid, to avoid absorbing radioactive iodine and then to develop thyroid cancer.
- Hypothyroidism secondary to taking drugs, for example: antithyroid agents, normally used in clinical practice to treat primary hypothyroidism; lithium,
normally used in the psychiatric-neurological field to treat certain mood disorders, some bipolar forms, blocks the synthesis of thyroid hormones;
tyrosine-kinase inhibitors, which in recent years have taken great place in the therapeutic field for the treatment of neoplastic diseases, as they fall into
those treatments that target cancer therapy, or even in the treatment of chronic diseases as well as in the rheumatological field as in some forms of rheumatoid
arthritis.
- Tumors: t. hypophyseal, hypophyseal adenomas, often associated, by compression ab estrinsecum on the secretory TRH cells with reduced secretion of TRH and
therefore secondary hypothyroidism. Craniopharyngiomas or meningiomas that are obviously not tumors involving hypophyseal or hypothalamic tissue, but still
create a compressive and also infiltrative damage to the hypothalamic-pituitary region.
- the traumas: surgical, from road accident, in the clinical field represent an important anamnestic data. You have to ask if you had traumas with cranial
trauma when you were a child.
- both necrotic and hemorrhagic vascular events
- infectious, infiltrative facts: sarcoidosis
- autoimmune disease: chronic pituitary lymphocytosis is the sister of chronic
lymphocytic thyroiditis. It is the same condition only that it is at the
pituitary level, there is a lymphocyte infiltrator that attacks the pituitary
gland
-congenitis: hypophyseal hypoplasia; Sept-optic dysplasia
- TSH secretion defect. Generally the causes are:
a) mutations in the TRH receptor genes
b) beta subunit mutation of TSH, which is the subunit through which TSH performs
its action at the thyroid level.
c) mutation of a series of pituitary transcription factors
d) drugs (glucocorticoids, beta carotene, dopamine, L-T4 therapy, obviously cause secondary hypothyroidism.T-T4 therapy, because the thyroid hormones given
by mouth suppress the secretion of TSH by negative feed-back, and that's that is normally done in patients with nodular therapy, for example in patients operated
for thyroid cancer in which you want to ensure that TSH which is a growth factor does not go to stimulate the residual disease)
The rarer forms are the peripheral ones, they are due to:
Genes involved in or in thyroid hormone transporters or receptors.
At the base of the pyramid by frequency are the causes of primary hypothyroidism,
due to a primitive problem of the thyroid gland; follow the central ones; and
then the peripheral ones.
Frequency of hypothyroidism.
It is greater than hypothyroidism in females, compared to the frequency with which it occurs in male patients. Often there is an association with thyroid
antibodies, specifically anti-thyroperoxidase antibodies, which are the most representative antibodies to hypothyroidism on an autoimmune basis. There is
also a fairly characteristic trend over the age. It generally starts between third and fourth decade, then obviously depends on the forms, because for
example there is chronic lymphocytic thyroiditis that appears in the pediatric age 2-3 years. This we say is a global trend of hypothyroidism, with a
deflection towards 60 years and then there is the greatest peak of primary thyroid dysfunction, which is in senile age.
clinic
Generally the appearance of the hypothyroid patient is characterized by edema, imbibition of the subcutis; a much more marked picture in which endocrine
ophthalmopathy coexists, is associated in autoimmune forms, both in Hashimoto's thyroiditis and in Basedown's disease. We can have a form called "subclinical
hypothyroidism" very mild, with very nuanced signs and symptoms up to very severe hypothyroidism, with marked signs and symptoms, which can also be fatal
when it comes to the hypothyroid coma.
The Spectrum of action of the thyroid hormones is ubiquitous, they act on all
the tissues and on all the organs. Let's start with the most obvious and
quickest action:
They are the hormones that guarantee the basal metabolism, obviously a hormonal
deficit translates into a reduction of the basal metabolism, reduces energy
expenditure, consumption of O2, the use of energy substrates (carbohydrates,
lipids, proteins), there is a progressive increase in body mass, of about 10%,
due both to an increase in fat mass, and to a real tissue imbibition, due to a
significant increase in water retention; thermogenesis is significantly reduced,
which also has repercussions from the clinical point of view, as hypothyroid
patients like the classic patients who do not tolerate cold, vice versa
hyperthyroid patients have a significant increase in thermogenesis and are those
who do not tolerate the heat . The intestinal absorption of glucose is reduced,
even the action of insulin is reduced, because obviously it is counterbalanced
by a lower use of glucose. While fasting blood glucose levels and fasting
insulin levels are practically almost superimposable between a hypothyroid and a
euthyroid subject, however, in clinical practice we find that diabetic patients
who become hypothyroid, we find ourselves often having to reduce the share of
insulin.
From the point of view of lipid metabolism, a typically atherogenic picture is
created, because it increases the total cholesterol and the share of LDL
cholesterol, low-density lipoprotein, generally those responsible for
transporting cholesterol from the liver to the periphery, so they have a
important atherogenic meaning. From the protein point of view there is a
reduction in protein synthesis and degradation, this means that it increases (?)
The total protein pool, there is a reduction in glycosaminoglycans, increases
interstitial edema and this also explains the edemigenous aspect , mostly
ubiquitous, of the hypothyroid subjects, in fact the edema involves the subcutis,
the serous, at the pericardial level, in fact these are patients who develop
pericardial effusion, pleural effusion and the edema also goes to the articular
level.
The cardinal signs of the hypothyroid facies:
-Rarrow eyebrows, cloudy facies, for edema and imbibition of the subcutis, plump
cheeks, prolapsed edema, pale appearance, even jaundice-like. There is eyelid
edema and ptosis of the eyelids. The skin is dry and mixedema, present in 90% of
cases. The most associated sign in absolute, the reason why many patients come
to perform an endocrinological visit is the increase in weight that can be
associated with a long history of hypothyroidism, the increase, not dramatic of
body mass, is about 10 %. The voice is low, it becomes a hoarse voice, like
hoarseness, especially if the hypothyroid condition has long been inveterate.
Bradipsychism is present: see the facies of a person who has an associated
cognitive deficit, bradylia, which is a more clinical sign.
Thyroid hormones, and specifically T3, which is the active hormone, under normal
conditions, increase tissue thermogenesis, there is a reduction in vascular
resistance, it reduces diastolic pressure, this involves an activation of the
renin-angiotensin system -aldosterone, increased pre-load at cardiac level,
which leads to an increase in stimulation of secretion of erythropoietin and
this eventually leads to a lowering of post-loading and chronotropic and
positive inotropic effect with increased cardiac output.
In the case of hypothyroidism, the opposite is the case. It reduces the
contractility of the heart, reduces the heart rate, in fact hypothyroid patients
tend to be bradycardic, increase peripheral vascular resistance, reduce the
volume of circulating blood, increases capillary permeability and this together
with the effect on the protein metabolism , extravasation increases and
therefore the typical edema of these patients.
Symptoms: dyspnea; there is a reduced tolerance to the physical effort,
therefore angina from myocardial suffering for reduced quantity of O2, that we
classically find with a low heart rate, then bradycardia, diastolic hypertension
and a whole series of other more frequent signs, not always constantly present
they depend on the severity of hypothyroidism. Surely the cardinal sign that is
never lacking is bradycardia and also asthenia is important.
Nervous system disorders are the most heterogeneous, confusingly with many other
conditions. Just think of a depressive disorder, a panic disorder, they are
often interchanged. The most frequent symptoms are headache, paresthesia, carpal
tunnel syndrome, which affects up to 5% of patients, the cause of which is
attributed to patients with untreated hypothyroidism over time.
Among the certainly more serious disorders we will have cerebellar ataxia,
vertigo or tinnitus, cognitive disorders, these are very important, have very
serious consequences, when hypothyroidism occurs during pregnancy, as the
thyroid hormones are responsible for many aspects, such as neuronal migration.
It follows that a hypothyroidism during pregnancy can give sequelae that can go
from cretinism, the classic cretinism from hypothyroidism, which fortunately now
almost no longer exists because we do the neonatal screening for congenital
hypothyroidism, to much more nuanced forms such as so-called DHD disorder, that
is the attention deficit and hyperactivity of the child, that is apparently
normal children, but in reality school age, 7-8 years, they are restless, they
can not follow the lessons, and they have problems in learning, but in fact they
are not children with a real cognitive delay, it is very nuanced disorder. This
explains why all pregnant women, especially in our areas of iodine deficiency,
must be followed for thyroid function.
obviously here we are talking about serious and important forms of
hypothyroidism. We can observe:
- Mixedmatous madness, linked to a mexedema, imbibition of the brain tissue,
which by mixed pictures of psychosis and schizophrenic disorders. Obviously very
rare forms.
- Depressive disorder, very common: even a mild hypothyroidism, perhaps
misunderstood, undiagnosed, which come after 6-7-8 months or 1 year visiting and
among the various disorders also have a depressive disorder. In those who are
familiar it is easier to manifest themselves.
At the gastrointestinal level there is basically a slowdown with
hypoperistaltism. On the one hand for the reduction of caloric intake, so they
are patients who eat less. On the other hand, peristalsis is reduced, without
the stimulation of thyroid hormones. So they are patients with a constipation,
constipation picture. Often coexist in the forms in which there is an
hypothyroidism on an autoimmune basis, chronic lymphocytic thyroiditis, also
another spectrum of autoimmune diseases involving other glands, for example
atrophic gastritis, in which there is achloride, is also associated, by attack
directed by antibodies of gastric parietal cells, thus reduced ac production.
Hydrochloric, with also digestive problems.
For reduced stimulation (by the thyroid hormones) there is also a lengthening of
the gastric emptying time: which can be associated with nausea or vomiting.
The diagnosis is basically a biochemical, laboratory diagnosis.
Basically we distinguish three degrees of hypothyroidism:
a) I phase, sub-clinical hypothyroidism: so-called because the free fractions,
FT4 and FT3 are perfectly normal, the only thing that changes is the TSH, for
feed-back tends to increase, because for an event that disturbs homeostasis of
our body, thyroid hormones are hyperstimulated by TSH to be produced in greater
quantities, ensuring homeostasis. Here we will find a normal FT4, and a T3 that
can be normal or even slightly increased, because the T3 has three iodine atoms,
the T4 has four, so in a glandular economy mechanism, it is better to produce a
thyroid hormone at less atoms of
iodine that not one that has more. This is the classic mechanism of adaptation
that occurs in areas of iodine deficiency, such as our Mediterranean area.
b) Hypothyroidism in the second phase: at this point we will have a high TSH,
the FT4, however, lowers and this is already a diagnosis of hypothyroidism, but
mild, obviously linked to the values of FT4, (which may be more or less low,
but also zeroed). The T3 always for the first mechanism, we can still find it in
the norm. We must remember that the T3 that we find in the circulation is a T3
that mainly comes from peripheral conversion, it is not a T3 from glandular
production, the thyroid gland produces more T4, which is the inactive hormone,
then thanks to peripheral desiodases, according to tissue needs, will be
converted into T3.
b) Third phase, that of severe hypothyroidism, the share of FT4 produced becomes
so low that even peripheral desiodases have only to convert. So we will have a
low FT4 and a low FT3, the TSH always remains increased.
After seeing the patient, the first thing that is done is the dosage of thyroid
hormones. The dosages of all that panel of hormones that were done 20-30 years
ago and that someone still persists in doing are no longer done. First of all,
only TSH is dosed and we also have the FT4 because in Europe there is still a
discourse linked to a problem of iodine deficiency, so it is always good to
associate a dose of FT4 to be associated with TSH. Obviously, even if both are
normal, FT4 and TSH, they give us the idea of:
-TSH high with normal FT4 → sub-clinical hypothyroidism
-TSH low and FT4 low → central hypothyroidism
-TSH high and FT4 high → peripheral hypothyroidism.
In this case they are both others, because the thyroid works normally, the
pituitary works normally, the thyroid hormones, on the other hand, do not work
normally. Given that there is a tissue hypothyroidism, TSH is hyperstimulated to
stimulate the thyroid, so it happens that we have a picture of hypothyroidism,
but it might seem like hyperthyroidism on a central basis, so it's like there's
an adenoma that
stimulates the thyroid, but in fact, the signs and symptoms are hypothyroidism.
In the forms of resistance, the therapy is that with thyroid hormones, there are
doses over-ceilings of thyroid hormones, administered to overcome the peripheral
resistance.
This picture of hypothyroidism, however, can also be found in a TSHoma, ie
secreting TSH hypophyseal adenoma. The TSH is high because produced by an
adenoma and is not regulated by feedback and is always high and the FT4 is also
high, because the thyroid is stimulated by the TSH produced by the pituitary
adenoma. So it is the same biochemical picture of a central hyperthyroidism, the
only one
difference is that, when there is middle adenoma, TSH values are very high. To
verify the presence of adenoma, the MRI is done, as well as a hyperthyroid
clinic; the patient has headaches, there may also be visual problems for
compressions on the optic nerve. "
At this point we understood that there is hypothyroidism but the investigation
continues:
if it is a thyroid problem, let's study the thyroid gland, if there is a suspect
of a central problem, let's study the hypothalamus-hypophysis axis. So the
suspicion that there may be adenoma, or neoplasm, or an empty saddle, when there
is the pituitary tissue that is going to herniate, then the saddle turcica is
filled by liquor, so you lose a good part of the pituitary function, is a
another cause of global glandular hypofunction, then hypopituitarism when it is
single or panhypopituitarism when all the tropins produced by the hypophysis are
involved.
Obviously, the anamnestic part is also very important. Meanwhile, if there is a
familiarity for thyroid diseases, which are familiar, but not all. Thyroid
nodules are not familiar, they are an acquired condition, linked to mechanisms
then of iodic deficiency, for which nodularity is created. The diseases that are
familiar are those autoimmune thyroid, such as chronic lymphocytic thyroiditis,
Basedown's disease, neoplastic diseases of the thyroid, differential thyroid
tumors, medullary thyroid carcinoma.
Excess iodine can be a problem for the thyroid, consider that there are drugs,
such as amiodarone which is loaded with iodine, which systematically due to
thyroid problems, because given
for months it accumulates in the tissues and problems on the function of the
thyroid gland, which can then
be of hypo or hyperthyroidism. "
The iodized salt does not disturb from this point of view, rather for pregnant
women now in the guidelines it comes from supplementation of tablets containing
iodine, about 250 micrograms a day, throughout pregnancy and is continued for
postpartum, in such a way that, if the woman nurses milk, she passes it on to
the child. So let's say that iodized salt is an aid, because many of us, unless
we eat shellfish, crustaceans, all foods very heavy iodine, we can not fill the
normal need. Then for personal reasons, there are those who will easily develop
a glandular hypofunction and who does not. From the European consensus now
iodized salt would also go to restaurants, they should give iodized salt. Foods
added with iodine? They are starting to create iodized cheeses, milk with iodine.
Iodine addition is not a risk. Indeed to those whose thyroid has been removed,
or has chronic thyroiditis, iodized salt does or does not change it. But in the
stage of development, children, but also people of 50-60 years who are still
euthyroid, enrich their diet with iodine is useful, also because, I repeat, the
Mediterranean basin is still deficient in iodine, especially the South -Italy.
Returning to the anamnestic examination, we need to assess if there are signs or
symptoms that can make us think of a central hypothyroidism, and therefore that
of a mass. Scotomas, headaches, generally frontal, which generally have a
progressive course. Obviously the physical part, the clinical examination, the
physical examination is important. is there or is not the goiter? The goiter may
be present in those forms of old hypothyroidism, especially in the pediatric age,
difficult in the adult where the gland is already formed, but for example in
children when they have chronic lymphocytic thyroiditis, Hashimoto's thyroiditis,
often the goiter it is an important clinical sign that correlates with the
disease.
Thyroid ultrasound is obviously important, in cases of primitive hypothyroidism
-RMN: in case of suspicion of central hypothyroidism, for a study of the
hypothalamic-hypophyseal region.
Second level molecular investigations: when there are those forms of peripheral
resistance, or even of thyroid dysgenesis, this is generally done in pediatric
studies to see if there are genetic defects, possibly to be investigated.
Now let's go to the big part of the causes of primary hypothyroidism,
thyroiditis.
Thyroiditis (SEE> THYROIDYES)
Thyroiditis is a broad spectrum of inflammatory or infectious diseases of the
thyroid gland.
We can divide them into three classes:
Acute → generally have a bacterial etiology and are very rare.
Sub-acute → viral, they are rare. However, they are still seen in clinical
practice, one a year.
Chronic → on an autoimmune basis.
What is the therapy in patients with hypothyroidism in general, regardless of
the cause?
This depends on the majority of glandular hypofunction, they are
treated with the final hormone, in this case it is eutiroxin, T4. The doses
oscillate from 1.4. 1.6 micrograms / kg / day in young-adult age (12 months -60
years), this is the posology swing that is considered. Generally the dosage
begins to prescribe always at full dosage, but in a subject of 50-60 years,
especially if it already has a basic cardiac disease, it begins with a
progressive dosage that increases from week to week. Because the thyroid
hormones have as basic almost immediate effect that of cardiac stimulation. The
T3, which is the active hormone, has a very short half-life, as soon as you give
it, if you miss the dosage you have symptoms of hyperglycular hyperfunction, so
you give preference to T4. Then, similarly to endogenous T4, it will be
converted by desiodases into T3, according to the needs of the organism. T4 is
very elastic, if you do not take for two days, there is no risk of having
problems with hypothyroidism or major deficits, precisely because T4 has a
half-life of days and tends to accumulate. T3 is associated in patients with
hepatic problems, where hepatic type II desiodase
there is therefore no conversion from T4 to T3, in fact they are patients who
become hypothyroid because they have a good T4, because we introduce it, but
they can not convert it. Usually there is a mixed therapy, where the greatest
quantity is always T4. Another circumstance in which it is from the T3, is a
slice of the tire-thetomized patients who complain after a couple of months of
the intervention to take weight and be tired. The T4 is controlled and is normal
and the T3 is basically low. This is because in these patients there are defects
of peripheral conversion of mixed therapy T3 and T4.
The TSH values that are used as therapy targets vary in age:
- from neonatal age to about 50 years → 1 microgram - 2.5 micrograms. Reference
values that yes
they use in clinical practice and they are not the ones that report the lab
sheets, because those
include a very wide range, which includes both hyperthyroidism, then TSH
suppressed,
that hypothyroidism.
Regarding the posology, they are considered in adulthood:
-consider that in the newborn in which there is congenital hypothyroidism, the
doses are 10-15 micrograms / kg. Doses excessive, massive, if you consider a
child who weighs a few Kg.
-for the adult takes 1.6 -2 micrograms maximum
Patient with thyroid cancer: slightly higher doses and the reference ranges of
TSH are not lowered, suppressed.
In summary, here are the dosages of L-thyroxine in hypothyroidism
Subclinical hypothyroidism
Oral.
Adults: 1 mcg / kg / day.
Hypothyroidism during antithyroid therapy
Oral.
Adults: 50-100 mcg / day.
Thyroid differentiated carcinoma
Oral.
Adults:> 2 mcg / kg / day.
Goiter
Oral.
Adults: 100-150 mcg / day; 100 mcg / day in the prophylaxis of relapse after
strumectomy.
Boys (up to 14 years): 50-100 mcg / day.
Thyroid inflammation
Oral.
Adults: 100-150 mcg / day.