Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_2617_Библиотеки_им_академика_М_И_Перельмана
.pdf
332
https://t.me/medicina_free
M. Ciaccio et al.
Basal copeptin
<2.6 pmol/L
(with fluid deprivation)
Complete Central Diabetes
Insipidus
95% sensitivity
100% specificity
Copeptin after stimulation
<4.9 pmol/L
Partial central diabetes
insipidus
94% sensitivity
94% specificity
<21.4 pmol/L
(without fluid deprivation)
Copeptin after stimulation
(with plasma sodium
levels≥147 mmol/L)
Copeptin after stimulation
Primary polydipsia
94% sensitivity
96% specificity
≥ 2.4 pmol/L
(without fluid deprivation)
≥4.9 pmol/L
Nephrogenic diabetes
insipidus
100% sensitivity
100% specificity
Fig. 25.5 Timper etal. algorithm for the differential diagnosis of diabetes insipidus by copeptin, in association or not with the liquids deprivation.
(Copyright EDISES 2021. Reproduced with permission)
Fig. 25.6 Fenske etal.
algorithm for the differential
diagnosis of diabetes
First blood sample (fasting, after 8 hours of
fluid deprivation)
insipidus. (Copyright EDISES
2021. Reproduced with
permission)
Copeptin
<2.6 pmol/L
Copeptin
>20 pmol/L
Complete central
diabetes insipidus
Sensitivity:95% | Specificity:100%
Second blood sample: copeptin and
serum Na+ (morning, fasting,
after 8 hours of fluid deprivation)
calculation of copeptin index:
S-Na+ [at 16 hours]
Copeptin Index
<20
Complete Central
Diabetes Insipidus
Sensitivity:100% | Specificity:86%
Nephrogenic diabetes
insipidus
Sensitivity:100% | Specificity:100%
Primary polydipsia
Sensitivity:86% | Specificity:100%
25 Endocrine System
https://t.me/medicina_free
333
Baseline measurement of plasma ADH
without fluid restriction
>2 pg/mL
Nephrogenic DI
Signal in T1 absent
or small
Fig. 25.7 Algorithm for the differential diagnosis of diabetes insipidus
by ADH and magnetic resonance imaging. (Copyright EDISES 2021.
Reproduced with permission)
<1 pg/mL
Brain MRI
Normal T1
signal
DI Primary polydipsia
Alternatively, a differential diagnosis of diabetes insipidus can be made based on plasma ADH and MRI values
without water restriction (Fig.25.7).
Signs and symptoms of uncomplicated pituitary DI can be
treated with desmopressin, which selectively acts on ADH
receptors, increasing the urine concentration and reducing urine
ow dose-dependently. On the other hand, signs and symptoms
of nephrogenic DI can be treated with a thiazide diuretic and/or
amiloride in combination with a low-sodium diet.
Inappropriate ADH Secretion Syndrome
The diagnosis is made by exclusion, based on clinical history, laboratory data, and physical examination.
SIADH should be suspected inpatients presenting with
hypotonic hyponatremia associated with euvolemia, dened
as the absence of clinical signs of hypovolemia (tachycardia,
mucosal dryness) or hypervolemia (subcutaneous edema,
ascites).
Table 25.10
Serum Sodium
Urine Osmolality
Laboratory parameters for SIADH diagnosis
Parameter SIADH diagnosis
<135mmol/L
Hypo-osmolality
Potassium
Urea
Uric acid
Creatinine
Thyroid hormones
Cortisol
Aldosterone
Glucose
Sodium
Fractional uric acid
excretion
<285mmol/L
Normal
Normal
Normal
Normal
Normal
Normal
Normal
Normal
Urinary > plasma
>40 mmol/L
12%
Table 25.10 shows the laboratory tests for the preliminary
diagnosis of SIADH.
Other laboratory tests helpfulfor SIADHdiagnosisare:
• Inability to eliminate a water load with urine (healthysubjects eliminate with urine more than 80% of the water
load within 4 hours, with urinary osmolality
<100mOsm/L).
• Hypouricemia due to volume expansion and the action of
ADH on renal ADH receptors that increases uric acid
clearance. Recently, an algorithm based on assessing
copeptin levels has been proposed to detect SIADH
(Fig.25.8).
Treatment of SIADH depends on the underlyingcause.
Hyponatremia is corrected by continuous infusion of hypertonic saline (NaCl 3%), which may be combined with loop
diuretics. If the cause removal is not possible or has been
followed by resolution of the SIADH, permanent treatment
is indicated. The treatment of the rst choice is uid
restriction.
334
ADH secretion syndrome
u-Na+, urinary sodium; u-Osm, urinary osmolarity.
Hyponatremia
https://t.me/medicina_free
Hypotonic urine
M. Ciaccio et al.
(Na+ <135 mmol/L)
Rule out pseudohyponatremia*
and non-hypotonic
hyponatremia**
u-Osm <300 mOsm/L
and copeptin <3 pmol/L
PP
Reduced effective
arterial volume
u-Na*<30 mmol/L u-Na*>30 mmol/L
Non-Euvolemic
Patient
Sodium depletion
(diarrhea, vomiting,
renal sodium loss)
Measure u-Osm and copeptin
u-Osm >300 mOsm/L
and/or copeptin >3 pmol/L
evaluate u-Na
Assess copeptin/u-Na
Sodium expansion
(heart failure, cirrhosis,
nephrotic syndrome)
+
+
ratio ×100
Non-hypotonic urine
Preserved effective
arterial volume
Rule out kidney disease
and use of diuretics
<30>30
Secondary
Hypocorticosurrenalism
or SIADH
Euvolemic
patient
*Assess triglycerides, total cholesterol, total protein; **assess urea, blood glucose.
Effective p-Osm = 2 × (s-Na++ s-K+) + glycemia/18.
K+, serum potassium; Na+, serum sodium; PP, primary polydipsia; SIADH, inappropriate
Fig. 25.8 Algorithm for the differential diagnosis of hyponatremia based on copeptin. (Copyright EDISES 2021. Reproduced with permission)
Thyroid
Two parathyroid glands are posterior to each upper and
lower pole of each lobe.
MarcelloCiaccio, GiuliaBivona, LuisaAgnello and
BrunaLoSasso
The thyroid gland originates from the pharyngeal oor
during the third week of gestation and is localized in the neck
region, migrating from the foramen caecum along the thyroglossal duct. At the 11th week of gestation, the synthesis of
Anatomy
thyroid hormones begins.
Vascularization of the gland is provided by the thyroid
The thyroid is a gland consisting of two lobes placed in the
anterolateral part of the trachea, connected by an isthmus,
immediately below the cricoid cartilage. Sometimes a
pyramidal lobe originates from the isthmus, extending superiorly on the midline.
arteries, two superior and two inferior; the recurrent laryngeal nerve runs at the lateral margins of the thyroid gland.
Microscopically, the thyroid gland is made up of follicles
composed of a layer of polarized cells (thyrocytes), which
protrude into the lumen of the follicle; this is entirely lled
25 Endocrine System
https://t.me/medicina_free
335
with colloid, a liquid, homogeneous and viscous substance
which contains high quantities of thyroglobulin, a protein
indispensable for the synthesis of iodothyronines.
In the context of the entire glandular parenchyma, neural
crest-derived cells, or C cells, are scattered throughout the
glandular parenchyma; however, they are present in greater
density at the junction of the superior and inferior thirds of
the thyroid gland. C cells, also called parafollicular or medullary cells, produce a hormone, calcitonin, which, under
certain paraphysiologic or pathologic circumstances, causes
a reduction in blood calcium levels.
Thyroid Hormones
Biosynthesis andSecretion
Thyrocytes produce two hormones, triiodothyronine (T3)
and tetraiodothyronine or thyroxine (T4). They are iodinated
thyronines containing a phenolic ring and one to four iodine
atoms. The biosynthesis of thyroid hormones requires tyrosine and iodine and consists of four steps:
• Active transport of iodide on the thyrocyte basement
membrane
• Oxidation of iodide
• Covalent bonding with tyrosine residues (organication)
leading tothe production of tyrosines (monoiodotyrosine
[MIT] and diiodotyrosine [DIT])
• Coupling of tyrosines and subsequent formation of T3
and T4
Thyroid-stimulating hormone (TSH) promotes these biosynthetic steps and secretion.
The daily iodine requirement to produce 100μg/day of T4
is 100–150μg. Most available supply comes from thedeiodination processes. Although iodine is relatively scarce,
small amounts can be taken up with water and food.
Perchlorate and pertechnetate can act as substrates for the
iodide transport system, acting as competitive inhibitors.
After entering the thyroid gland, iodine is transported to
the apical membrane of the follicular cells, where the enzyme
thyroperoxidase (TPO) mediates its oxidation. TPO is a
heme-glycoprotein consisting of 933 amino acids, with a
molecular weight of 107 kDa, located at the microsomal
level and whose substrate is represented by hydrogen peroxide. In addition to catalyzing the iodineoxidation, which is
followed by its organication in the tyrosine residues of thyroglobulin (Tg), TPO also mediates the formation of the
ethereal bond between the iodotyrosine of Tg, leading to T4
and T3synthesis. TPO is stimulated by TSH and inhibited by
perchlorate, pertechnetate, and thiocyanate (Fig. 25.9).
Thyroglobulin contains approximately 100 tyrosine residues, 2–3 T4 residues, and 0.2 T3 residues (one residue for
every ve molecules). Although several other proteins contain larger amounts of tyrosine, and although all of these can
be iodinated, the synthesis of thyroid hormones is exclusive
to thyroglobulin.At the origin of this mechanism lies the primary structure of the glycoprotein: the coupling of MIT and
DIT takes place only at specic amino acid sequences present on thyroglobulin subunits.
In order to release thyroid hormones into the circulation,
thyroglobulin must be reuptake from the thyrocyte to undergo
enzymatic hydrolysis, following which T3 and T4 diffuse
into the extracellular uid and then into the vascular torrent.
During this phase, T4 is deiodinated to T3, and iodide is
largely recycled into the thyrocyte.
Approximately 80% of T4 is metabolized through deiodination. Of this, 40% is converted to T3, and the remaining
40% to reverse T3 (rT3). The bulk of T3 obtained by deiodination is formed at extratiroid sites (80%), mainly in the
liver and kidney. Peripheral deiodase activity can be found in
all tissues, where it locally modulates the bioavailability of
T4; this peripheral regulation by deiodinases can determine
systemic effects and representsan alternative control mechanism to the classic endocrine axis.
The process of deiodination will inactivate T3 with the
formation of T2, which has no biological activity.
The deiodination process is catalyzed by 5′-deiodase, a
microsomal enzymatic activity of which three isoforms are
known. The isoform most commonly found in the liver, kidney, and thyroid is deiodinase I, which removes iodine at the
outer ring of T4, and, then, converted to T3. In the brain and
on the skin, deiodase II catalyzes the same reaction.
Deiodinase III, distributed almost ubiquitously, has a fundamental role in the degradation of T3 into T2 and T4 into rT3,
an inactive compound with two main functions: regulating
the excess of thyroid hormones and glandular secretion by
inhibiting deiodinases I and II (Fig.25.10).
Specic deiodination pathways can be found in many
organs and tissues; for example, deiodinase III is well represented in the placental and glial areas; deiodinase II is very
active in the brain and functions even in conditions of
reduced glandular secretion. For this reason, in hypothyroidism, a discrete production of T3 of encephalic origin is maintained, even in the presence of reduced serum T4.
Deiodinases regulate the activity of thyroid hormones
locally in response to mainly environmental stimuli. The
local control of the bioactivity and bioavailability of thyroid
hormones, mediated by peripheral deiodinases, independently anks the central control of the hypothalamic- pituitary
336
Follicular cell Plasma Follicular lumen containing colloid
T3
https://t.me/medicina_free
M. Ciaccio et al.
Na
+
–
I
2 Na
–
I
+
Lysosome
T3 and T4
colloid
Basal
membrane
Fig. 25.9 Synthesis of thyroid hormones. A Na+ symport protein on
the apical membrane of follicular cells mediates the active transport
within the follicular cell of two sodium ions and an iodine molecule.
Pendrin, a protein expressed on the apical membrane of follicular cells,
mediates the transport of iodide from the cytoplasm to the follicular
lumen. Thyroid peroxidase (TPO), located on the apical membrane of
follicular cells, mediates the oxidation of iodide and its organization in
tyrosine molecules linked to thyroglobulin, leading to the formation of
monoiodiothyroisin or diiodiotyrosin (MIT and DIT); the TPO also
mediates the coupling of two iodized tyrosines leading to the formation
CH
I
OH
2
I
I
MIT
OH
2
I
DIT
OH
2
I
I
OH
I
TPO
Iodinated tyrosines
–
I
CH
2
CH
CH
Thyroglobulin
I
DIT + MIT =
CH
CH
CH
2
2
O
2
I
I
CH
2
I
OH
I
I
O
I
DIT + DIT = T4
OH
Apical
membrane
of T4 (DIT + DIT) or T3 (MIT + DIT). Once iodized, TG accumulates
in the follicular lumen as a colloid. Through the colloid pinocytosis at
the level of the apical margin of the follicular cells, the colloid is reabsorbed and will appear as droplets within the cytoplasm. The colloid
droplets move toward the basement membrane and fuse with the lysosomes; the lysosomal proteases will lead to the degradation of the colloid with the release of T3 and T4. The nal phase is represented by the
secretion of free iodothyronines T4 and T3in the blood. (Copyright
EDISES 2021. Reproduced with permission)
Fig. 25.10 Thyroid hormone
metabolism. (Copyright
T4 Metabolism T3 metabolism
EDISES 2021. Reproduced
with permission)
40%
T4
Thyroid
20%
endocrine axis and can generate systemic effects, such as
acclimatization and appetite. In other words, serum T4
concentrations are controlled by the central axis but functionally also by local deiodinases.
Catabolism of thyroid hormones occurs in the liver, where
a process of glucuronidation allows their intestinal elimination as glycuronates (Fig.25.10).
Liver
40%
Kidney
T3
rT3
80%
T3
20%
Thyroid
Glucoronates
Glucuronates
Liver
Regulation ofThyroid HormoneSecretion
andTSH
Regulation of thyroid hormone secretion is an example of
endocrine feedback of the hypothalamic-pituitary-target
gland axis. The synthesis and release of T4 and T3 closely
depend on the secretion of pituitary thyrotropin, TSH, which
varies sensitively and linearly with changes in serum T4 and
Hypothalamus
T4/T3
https://t.me/medicina_free
25 Endocrine System
Hypothalamus
TRH
Pituitary
Pituitary
Thyroid
Fig. 25.11 Hypothalamic-pituitary-thyroid axis and retroregulation or
negative feedback. (Copyright EDISES 2021. Reproduced with
permission)
Thyroid
TSH
T3. This inversely proportional variation between TSH and
T4 expresses the retroregulation, or negative feedback, upon
which the functioning of the endocrine axis is based
(Fig.25.11). Secretion of TSH (and thus thyroid hormones)
is stimulated by the thyrotropin-releasing factor, TRH, produced in the hypothalamus and inhibited by T4, T3, and
TSHexcess. Laboratory diagnosis of endocrine pathologies
uses the negative feedback system: to detect alterations in
thyroid secretion, serum TSH is initially determined.
TSH is a glycoprotein produced in the adenohypophysis
that stimulates the synthesis and release of thyroid hormones.
TSH consists of two distinct subunits, α and β; the former is
common to other pituitary tropins (FSH, LH, human
Chorionic Gonadotropin [hCG]), while the latter expresses
the specic biological activity of the hormone. TSH secretion occurs by spontaneous uctuations in a periodic pattern
of 1–2hours (pulsatile rhythm) and a morning peak before
waking up (circadian rhythm). The normal reference values
of TSH are between 0.4 and 4 mU/L; its half-life is
30minutes.
Transport ofThyroid Hormones
More than 99% of T4 and T3 circulate reversibly bound to
some serum proteins: Thyroxine-Binding Globulin (TBG),
which carries the largest fraction of both T4 and T3 (75%
and 80%, respectively); prealbumin, formerly known as
Thyroxine-Binding PreAlbumin (TBPA) or transthyretin
(TTR); albumin; and lipoproteins. TBG is a 415 amino
acid polypeptide whose gene is located on the X chromosome. It is synthesized in the liver and belongs to a superfamily of serine protease inhibitors known as serpins (from
serine protease inhibitors). The afnity of TBG for thyroid
337
hormones is 50 times greater than that of prealbumin and
7000 times greater than that of albumin. TBG can undergo
cleavage by leukocyte elastase at sites of inammation,
with a reduction in its afnity for T4 and T3. Transport
proteins maintain an extratihyoid pool of T4 as stable as it
is large to prevent sudden depletion of circulating quotas;
they also provide protection in the presence of urinary
iodine losses.
Alterations in TBG, albumin, and prealbumin affect total
circulating T3 and T4 levels. Pregnancy and estrogen use
cause an increase in serum levels, while nephrotic syndrome,
androgens, and glucocorticoids cause a decrease. Many other
drugs can interfere with the binding between thyroid hormones and transport proteins (barbiturates, heparin, furosemide, salicylates, 5-uorouracil). Free circulating thyroid
hormones (fT4 and fT3), which are not affected by changes
in serum proteins, carry out biological function; fT3 and fT4
concentrations are, respectively, 2.5–4.5 pg/mL and 0.8–
1.8ng/dL.
Mechanism ofAction ofThyroid Hormones
Thyroid hormones bind to specic receptors (TRs) in the
nucleus of most cellular and tissue districts. They belong to
the superfamily of receptors for steroid hormones and mediate most of the biological actions of T3 and T4; almost all of
the hormone bound to the nuclear receptor is represented by
T3, which constitutes the activated hormonal form, while T4
is a pro-hormone, although endowed with intrinsic biological activity. At least two types of receptors are known, α and
β, each with two isoforms, α1 (TRα1) and α2 (c-erbAα2), β1
(TRβ1) and β2 (TRβ2). Some organs have numerous receptors (liver, pituitary gland), while others are sparsely represented (testis, spleen). Moreover, thyroid hormone’s
non-genomic (or early) actions are known, mediated by
mitochondrial and membrane receptors, mainly related to the
stimulation of second messengers; the mechanisms of action
mediating genomic and non-genomic effects are not completely independent.
The actions of thyroid hormones are crucial for the proper
performance of numerous physiological activities, such as
fetal development, oxygen consumption, thermogenesis,
positive inotropic and chronotropic effects, breath center
control, intestinal motility, erythropoiesis, central nervous
system (CNS) development, and function, skeletal turnover,
energy substrate metabolism, cholesterol metabolism, hair
system turnover; other effects of thyroid hormones include
increased metabolic turnover of other hormones and expression of adrenergic receptors on skeletal muscle, heart, adipocytes, and lymphocytes.
338
https://t.me/medicina_free
M. Ciaccio et al.
Laboratory Investigations
TSH, fT4, andfT3
Serum TSH concentrations vary markedly in response to
small changes in blood levels of T4 and T3. A rational
approach to assessing thyroid function is to determine TSH,
possibly accompanied by the measurement of thyroid hormones. The high sensitivity and specicity of serum TSH
assays justify their use in clinical practice as a screening test
for thyroid alterations. TSH measurement should be performed by high-sensitivity immunometric methods.
TSH assay may be required in the following cases:
• Screening of apparently healthy populations
• Diagnostic assessment of outpatients with clinical symptoms attributable to thyroid dysfunction
• Diagnostic investigation on the hospitalized patients with
clinical symptoms ascribable to thyroid dysfunction
• Monitoring the course of the diagnosed thyroid disease
and/or specic therapy (medical and/or surgical)
Adults with any of the following conditions are at high
risk for thyroid dysfunction:
• Previous history of thyroid dysfunction
• Goiter
• Previous history of thyroid surgery
• Previous history of cervical radiation therapy
• Autoimmune diseases: diabetes mellitus type 1, celiac
disease, etc.
• Use of drugs: lithium, cytokines, interferon, amiodarone,
contrast media
• Family history of thyroid disease or other autoimmune
diseases
• Chromosomal alterations: Down’s syndrome, Turner’s
syndrome, Klinefelter’s syndrome, etc.
• Alterations in laboratory tests suggestive of thyroid disease: hypercholesterolemia, hyponatremia, anemia,
hyperprolactinemia, hyper-CK, hyper-LDH, hyper-AST/
ALT, hyper-ALP, etc.
• Comorbidities: sleep apnea, depression,and dementia
For pediatric subjects, the following conditions are asso-
ciated with a high risk of thyroid dysfunction:
• Children/adolescents with short stature or low growth
• Children with pubertal developmental disorders
• Hyperactive children and adolescents
• Children and adolescents with reduced school
performance
With rare exceptions represented by TSH-secreting pitu-
itary adenomas and pituitary resistance to the action of thy-
roid hormones, the nding of normal TSH values excludes
the presence of alterations in glandular secretion.
Finally, when not mandatory, it is desirable to monitor
glandular secretion in the elderly, infants, and nursing
mothers.
The detection of an altered TSH value should be followed
by the measurement of fT4 and possibly fT3 in the same
sample (TSH-reex) (Fig.25.12). The use of prole or combination tests is reserved for the rare specic cases in which
the TSH test alone has no informative value (TSH-secreting
adenoma, thyrostatic drugs, suspected pituitary/hypothalamic diseases, resistance to the action of thyroid
hormones).
The widespread availability and pronounced sensitivity of
TSH immunoassays have rendered the TRH stimulus test
obsolete; the diagnostic signicance of non-elevation of
TSH after bolus (200–400μg) is thought to be the same as
that of suppressed TSH.Although assays for total T3 and T4
are available, it is appropriate to determine free fractions
(fT3 and fT4), unaffected by physiologic and pathologic
conditions associated with changes in binding between total
hormones and TBG1.
Physiological changes in fT3 and fT4 concentrations are
frequently found with age, during pregnancy, and in prolonged fasting.
In some circumstances, TSH determination alone can be
misleading, and its use as a screening test is contraindicated.
In particular, TSH-secreting pituitary adenomas and pituitary resistance to thyroid hormones can lead to elevated
TSH levels without hypothyroidism; on the contrary, TSH
suppression can occur during the rst trimester of pregnancy
as a consequence of hCG secretion, or as a consequence of
the pharmacological treatment of hyperthyroidism, or as a
consequence of the administration of several other drugs,
including dopamine and glucocorticoids. In any case, all
serious extra-thyroidal diseases can lead to increased TSH
levels.
It should be noted that the TSH value in thyroid function
screening is null in the presence of known pituitary disease
or only clinical suspicion of it.
Autoantibodies
The search for autoantibodies can complement the evaluation of thyroid function to make an etiologic diagnosis.
Antibodies directed against thyroperoxidase (TPOAb),
previously dened as antimicrosomal, have long been
used to diagnose hyperthyroidism. Although their use in
clinical practice is still widespread, the most updated literature recommends their determination only in subclinical hypothyroidism and in identifying the autoimmune
nature of thyroiditis. The assay of TSH anti-receptor antibodies (TRAb) has reached high standards of analytical
performance (third generation TRAb); in patients who do
causes
25 Endocrine System
https://t.me/medicina_free
339
Reference Range
TSH 0.4–4 mU/L
fT3 2.5–4.5 pg/mL
fT4 0.8–1.8 ng/mL
Normal
Subclinical
hyperthyroidism
Fig. 25.12 TSH reex: diagnostic algorithm of the main alterations of the glandular function. (Copyright EDISES 2021. Reproduced with
permission)
Normal
hyperthyroidism or
T3-thyrotoxicosis
fT3
High
Moderate
+ +
TRAb
+
TPO
Graves’ disease Hashitoxicosis Other
Low
fT4
High
Overt
Hyperthyroidism
TPO and Ab TRAb to
identify autoimmune
etiology
TRAb
–
TPO
TSH
Normal
Euthyroidism
– –
TRAb
+
TPO
–
Overt
hypothyroidism
TPO Ab to identify
autoimmune etiology
TRAb
TPO
High
fT4
Low
causes
–
Other
Normal
Subclinical
hypothyroidism
+
Hashimoto's
thyroiditis
not present an obvious clinic, they are used in the differential diagnosis between Basedow–Graves and other
forms of hyperthyroidism. The measurement of TRAb is
also indicated in therapy monitoring of hyperthyroidism
to distinguish patients with a high probability of remission (80–100%) from those with a very low probability
(20%).
It should be noted that TPOAb and TRAb are not infre-
quently detected in the serum of euthyroid subjects (2–5%).
Today, antibodies directed against thyroglobulin have no
diagnostic value, and their determination is never
appropriate.
Diagnosis andTherapy
The main laboratory pictures of the disease are represented
by hyperthyroidism and hypothyroidism; both can present in
different clinical forms, and the diagnosis is based on laboratory ndings. Hypothyroidism has a prevalence of 4.6–8.9%,
while hyperthyroidism has a prevalence of 0.9–2.0%. Hyper-/
hypothyroidisms can be classied into primary, secondary,
and tertiary based on the location of the lesion (thyroid, pituitary, or hypothalamic, respectively). The diagnosis of secondary hyperthyroidism is suggested by elevated fT3 and
fT4 values together with increased TSH concentrations; tertiary forms of hyperthyroidism, as well as secondary and tertiary forms of hypothyroidism, are very rare.
The nding of suppressed serum TSH (<0.1mU/L) raises
the diagnostic suspicion of primary hyperthyroidism, and the
nding of elevated fT4 levels is sufcient to conrm the
diagnosis of frank hyperthyroidism. Evidence of normal fT4
levels associated with low TSH concentration are indicative
of subclinical hyperthyroidism; the determination of fT3
must conrm it. In 2–5% of cases of primary hyperthyroidism, in addition to the decrease in serum TSH levels, there is
only an increase in fT3 and not in fT4; this condition, termed
T3-thyrotoxicosis, most likely represents an early phase of
hyperthyroidism, i.e., moderate hyperthyroidism. On the
contrary, a very high TSH value (>10mU/L) suggests primary hypothyroidism, and its association with low fT4 levels
indicates overt primary hypothyroidism. In the presence of
elevated TSH concentrations and normal fT4 levels, the
diagnosis of subclinical hypothyroidism can be made without resorting to the determination of fT3, which, in more
than 25% of cases of hypothyroidism, does not show any
alteration; therefore, the measurement of fT3 in hypothyroidism is not appropriate (Fig.25.12). The anti-TPO antibody assay allows for the differential diagnosis between
Hashimoto’s thyroiditis (autoimmune-based hypothyroidism) and other forms of hypothyroidism.
Primary Hyperthyroidism
The most common clinical form is Basedow–Graves disease,
a multisystem pathology on an autoimmune basis, characterized by pathognomonic clinical signs such as exophthalmos
340
https://t.me/medicina_free
M. Ciaccio et al.
and pretibial myxedema. In most cases, Basedow’s disease is
accompanied by goiter, an enlargement of the gland which,
in this case, is non-nodular or diffuse. The hyperthyroid subject is clinically thin, tachylalic, tachypsychic, and insomniac. Less common forms of hyperthyroidism are toxic
multinodular goiter (TMG) and solitary hypersecreting nodule or toxic adenoma. As mentioned above, in the presence
of a clinical blur or non-nodular glandular enlargement, the
determination of TRAb allows the etiologic diagnosis. The
conditions of TMG and toxic adenoma are distinguished by
the character of functional autonomy of the nodular lesions;
on a laboratory level, this gives rise to the peculiar picture of
a disproportionate increase in fT3 compared to fT4.
These forms of hyperthyroidism are accompanied by thyrotoxicosis, a clinical syndrome resulting from an excess of
thyroid hormones; hyperthyroid patients always present with
thyrotoxicosis, but thyrotoxicosis may not result from
hyperthyroidism.
Treatment of hyperthyroidism can be ablative, radiation,
or pharmacological, depending on the nature of the lesion
that caused it.
Primary Hypothyroidism
The most common cause of hypothyroidism is Hashimoto’s
thyroiditis, an autoimmune disorder common in countries
with adequate iodine intake. Other causes of hypothyroidism
are iatrogenic and iodine deciency. Clinically, the hypothyroid patient is asthenic, overweight, bradylalic, and bradypsychic. Determination of serum TSH and fT4 is usually
sufcient to diagnose. It is helpful to determine the presence
of TPOAbto conrm the autoimmune etiology; the detection
of these antibodies is frequent in hyperthyroid subjects, and
their use in clinical practice also extends to Basedow–Graves
disease. In the early stages, Hashimoto’s thyroiditis may
present with thyrotoxicosis, dened as hashitoxicosis, due to
massive cell lesions with the conspicuous release of already
synthesized thyroid hormones. From a biochemical-clinical
point of view, it is characterized by hyperthyroidism and the
presence of anti-TPO antibodies. It is short-lived and usually
evolves toward spontaneous remission and, with time, toward
hypothyroidism.
Laboratory alterations of the hypothyroidism may affect
the lipid prole, up to frank dyslipidemia.
Treatment of hypothyroidism is always replacement
therapy.
Thyroiditis
Thyroiditis is an autoimmune, inammatory, or infectious
disease, which can be divided into acute, subacute, and
chronic diseases. Riedel’s chronic brous thyroiditis is rare,
as are acute suppurative forms due to pyogenes. Subacute
forms, which are relatively frequent, include Hashimoto’s
disease and De Quervain’s thyroiditis, which has a viral etiology. De Quervain’s thyroiditis, also called giant cell or
granulomatous thyroiditis, is characterized, from the point of
view of glandular secretion, by a succession of three phases,
which correspond to as many laboratory pictures. The rst
phase is thyrotoxic, with low TSH levels and high fT4 and
fT3 concentrations, and may be followed by a hypothyroid
phase, with a slightly increased or normal TSH concentration and low fT4 levels and, nally, the recovery phase, characterized by normal TSH, fT3, and fT4. The presence of
fever and pain and increased indices of acute inammation
suggest an infection as the cause of the disease.
Parathyroids
MarcelloCiaccio, GiuliaBivona, and LuisaAgnello
Anatomy
The parathyroid glands, four in number and weighing
approximately 40mg each, are located in the anterior region
of the neck, near the thyroid gland. They are usually arranged
symmetrically and in pairs on each thyroid lobe’s upper and
lower poles (Fig.25.13).
Microscopically, the gland consists of epithelial cells and
abundant adipose and brous stroma. Parathyroid epithelial
cells are divided into primary and oxyphilic, the former predominant. Each cytotype secretes a hormone that regulates
calcemia and inorganic phosphate homeostasis,
parathormone.
The parathyroids are supplied with blood by the parathyroid arteries, terminal branches of the inferior and middle
thyroid arteries; waste blood from the parathyroids ows
into the tributary veins of the thyroid gland.
Embryologically, the parathyroids originate from the dorsal endoderm at the end of the sixth week of gestation.
Parathormone (PTH)
Synthesis, Secretion, Metabolism,
andMechanism ofAction
PTH is a polypeptide produced and secreted by parathyroid
cells in response to certain secretagogue stimuli, the most
potent of which is ionized calcium. PTH is formed by 84
amino acids and, like all secretion proteins, is synthesized
from a larger precursor. This pre-pro-parathormone is
cleaved in the wrinkled endoplasmic reticulum forming the
pro-parathormone, a compound of reduced size that nally
will be converted, in the Golgi apparatus, in the mature
Pre-pro-PTH (115 aa)
Biologically active
NH
COOH
COOH
COOH
Thyroid
Parathyroids
Parathyroids
25 Endocrine System
https://t.me/medicina_free
Fig. 25.13 Parathyroid glands. (Copyright EDISES 2021. Reproduced
with permission)
2
(31 aa)
Pro-PTH (90 aa)
NH
2
(6 aa)
PTH (86 aa)
NH
2
341
and diacylglycerol), responsible for intracellular biochemical signals transduction.
The pattern of PTH secretion has a circadian rhythm (with
a peak around midnight) and an episodic rhythm (with uctuations at intervals of about 60minutes).
Although serum calcium is the primary regulator of PTH
secretion, other secretagogue agents include magnesium,
lithium, hyperphosphatemia, catecholamines, cortisol, histamine, dopamine, and alcohol.
In contrast, somatostatin, thyroid hormonesexcess, vita-
, FGF23 (broblast growth factor 23), calcium chan-
min D
3
nel blocker antihypertensive drugs, and aluminum
intoxication, inhibit PTH secretion.
FGF23 is a phosphoglycoprotein secreted by osteoblasts
and osteocytes in response to hyperphosphatemia and vitamin D3. Noteworthy, parathyroid cell possesses the vitamin
D3 receptor (VDR) and Klotho, which are sensitive to vitamin D3 and FGF23, respectively.
The role of magnesium is not fully known. It is a less
potent secretagogue than serum calcium, and under physiological conditions, its inuence on PTH secretion is
negligible.
Fig. 25.14 Biosynthesis of parathyroid hormone. (Copyright EDISES
2021. Reproduced with permission)
metabolite, the parathormone. The hormone’s biological
activity lies in the amino acid sequence 1-34, which forms
the amino-terminal fragment of PTH (Fig.25.14).
PTH synthesis, not its secretion, strictly depends on intra-
cellular calcium concentration.
Immediately after synthesis, PTH is stored in dense cytoplasmic granules from which it is secreted and in amino- and
carboxy-terminal fragments. The half-life of PTH is
5–10minutes; approximately 70% is metabolized in the liver
and the remaining 30% in the kidney. A negative feedback
mechanism regulates PTH secretion by plasma ionized calcium concentrations. Because plasma calcium concentrations must be maintained within very narrow limits, PTH is
extremely sensitive to changes in its concentrations.
Therefore, the relationship between the hormone and the cation is sigmoidal and represents a high-gain system since signicant changes follow small changes in plasma ionized
calcium in PTH secretion.
The sensitivity to changes in serum calcium concentration
by PTH, and therefore its ability to promptly correct abrupt
changes in calcemia, is due to the presence of a receptoron
the membrane of the parathyroid cell (Ca2+ sensing Receptor
[CaR]). The PTH/CaR interaction activates the adenylate
cyclase and phospholipase C signal transduction systems.
Via a CaR-coupled G protein, the hormone-receptor complex forms second messengers (cAMP, inositol triphosphate
Biological Actions
PTH’s biological role is to rapidlybuffer abrupt changes in
extracellular uid calcium levels. For example, the intermittent introduction of dietary calcium exposes one to uctuations in calcemia that, in the absence of PTH, would be
incompatible with life.
The biological activity of PTH is hypercalcemic and is
realized through a direct action on the kidney and bone; indirectly, PTH also acts on the enterocyte, modulating calcium
absorption. In particular, the hormone has a triple action at
the renal level. In the proximal tubule, it induces the excretion of phosphates, inhibiting their reabsorption by the Na+/
Pi co-transporter, and stimulates the activity of the enzyme
1α-hydroxylase, responsible for the conversion of 25(OH)cholecalciferol (calcidiol) into 1,25(OH)2-cholecalciferol
(calcitriol), or active vitamin D3, responsible for intestinal
calcium absorption; in the distal tubule, determines the rapid
reabsorption of calcium against the gradient and excretion of
phosphate.
Note that much of the 24-hour calcium reabsorption
occurs in the proximal tubule by a sodium-related and PTHindependent mechanism.
Slower, however, is the action of PTH on the bone, in
which the nal effect of the hormone signal is the stimulation
of the reabsorption of the matrix, with consequent release of
calcium salts into the circulation. This hormone action is
mediated by a receptor on osteoblasts, which stimulates the
anchorage of osteoclasts to the matrix through the secretion
of several immune-endocrine mediators (some examples are
IGF-1, IL-1, IL-6, TNF-α). As a result of the action of these
Соседние файлы в папке Библиотека им академика М.И. Перельмана