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342
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M. Ciaccio et al.
cytokines on osteoclasts, an acidic microenvironment is created at the interface between the osteoclastic plasmalemma
and the mineralized matrix, known as the rippled margin.
This is functionally assimilated to a lysosome, in which the
release of numerous lytic enzymes and, consequently, the
extracellular matrix’s erosion occurs. The calcium contained
in the crystalline hydroxyapatite is thus released into the circulatory stream.
Finally, in the enterocyte, PTH induces the synthesis of
active vitamin D3, which is responsible for intestinal calcium absorption.
Regulation ofCalcemia andCalciumPhosphorus Homeostasis
The total amount of calcium in the body is about 1–2 kg.
Over 98% of this is found in the mineral phase, i.e., in the
crystalline hydroxyapatite in the extracellular matrix of bone
tissue. One percent of skeletal calcium is exchangeable with
the organism in a cyclic alternation between theproduction
and degradation of the newly formed matrix that constitutes
bone turnover. In the formation phase, calcium is sequestered in the skeleton through incorporation into the matrix by
osteoblasts; in the degradation phase, which immediately
follows the previous one, calcium is released into the circulation by the degradation process of the same newly formed
matrix by osteoclasts (bone resorption). Bone metabolism is
based on the continuous alternation of the phases of formation and degradation described above; for this reason, it is
considered an extremely dynamic metabolism.
Reference values for calcemia are generally between 8.5
and 10.2 mg/dL; however, depending on the determinationmethod, they may vary up to ±0.5mg/dL.
This circulating share is divided as follows: about 50% is
free or ionized calcium and is biologically active; about 40%
is bound to plasma proteins (mainly albumin) and is biologically inactive; nally, about 10% is complexed in salts and is
also inactive. This distribution assumes importance in diagnosing calcemia alterations since variations in plasma proteins determine ctitious calcemia alterations.
Plasma calcium levels must be kept rigidly within the
upper and lower limits of the reference range since even
slight variations correspond to severe clinical effects.
The hormonal systems controlling calcemia are nely
tuned to keep calcemia consistently within baseline limits.
Homeostasis is regulated, under physiological conditions,
by PTH and vitamin D3, both of which have a hypercalcemic
effect. Calcitonin has a role only in paraphysiological and/or
frankly pathological conditions and is hypocalcemic.
As mentioned above, PTH plays a crucial role in correcting changes in calcemia promptly.
Table 25.11 Actions of vitamin D
Calcemic actions Maintenance of calcium and phosphorus
No calcemic
action
homeostasis
Control of cell proliferation (protein p21, p27)
Inhibition of neo-angiogenesis
Regulation of the immune system
Induction of cell differentiation and apoptosis
Vitamin D is a steroid hormone involved in numerous
processes, including maintaining calcium homeostasis
(Table25.11).
Vitamin D3 can be synthesized in the skin, starting from
7-dehydrocholesterol, by the action of ultraviolet rays, or
taken with the diet (Fig.25.15). Once in circulation, vitamin
D of endogenous and exogenous origin undergoes a rst
hepatic hydroxylation that converts it into 25(OH)cholecalciferol, or calcidiol, a biologically inactive form,
which undergoes a second renal hydroxylation, giving rise to
the biologically active form of vitamin D, 1,25(OH)2cholecalciferol, or calcitriol. The latter increases serum calcium and phosphate concentrations by three mechanisms:
• At intestinal level, it determines the synthesis of calbin-
dins, proteins involved in the absorption of calcium and
phosphate
• At the level of osteoblasts, it stimulates the expression of
the ligand RANK-L, which interacts with the RANK
receptor, expressed on resting osteoclasts, thus accelerat-
ing the process of bone resorption
• At the level of the distal renal tubules, itincreases the
reabsorption of calcium and phosphate
PTH-Related Peptide
PTH-related protein (PTHrP) is a 141 amino acid peptide
that exhibits a high degree of homology with PTH. It is
involved in bone growth during skeletal development through
regulating chondrocyte proliferation and differentiation. The
same receptor and transduction system mediate the biological activity of PTHrP as PTH.Hypercalcemia during neoplasia is associated with abnormal hypersecretion of PTHrP.
Phosphorus
The total inorganic phosphorus in a healthy adult is about
1kg, 85% in the skeleton. The circulating portion amounts to
2.8–4 mg/dL and is represented by free ions HPO42 and
NaHPO4. Only 12% of circulating phosphorus is bound to
plasma proteins, unlike calcium.
Although it is a constituent element of the skeleton, phosphorus is widely represented in all tissues, being involved in
all metabolic processes.
24,25-(OH)-D
Intestine
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Skin
UVB rays
7-dehydrocholesterol
Pre-
vitamin D
Vitamin D3Vitamin D
3
343
Vitamin D
rich foods
2
Vitamin D
Circulation
Osteoblast
1,25-(OH)
Fig. 25.15 Biosynthesis and calcemic actions of vitamin D.Vitamin D
can be synthesized in the skin following exposure to ultraviolet rays
(UVB) from the sun, which mediate the conversion of
7- dehydrocholesterol (pro-vitamin D) into pre-vitamin D3 (pre-D3),
which is converted into vitamin D
from foodasvitamin D
the chylomicrons and absorbed in the lymphatic system, through which
they reach the circulation, where they are bound to the vitamin D binding protein (DBP) and lipoproteins. In the liver, vitamin D undergoes the
and D3. After ingestion, they are incorporated in
2
by heat. Vitamin D can also come
3
-DBP Vitamin D3/D2 - Lipoproteins
3
-D
2
Liver
25-OH-D
Kidney
rst hydroxylation to 25-hydroxyvitamin D (25(OH)D), which, mainly
in the kidney, undergoes a second hydroxylation which converts it into
the active form, 1,25 dihydroxy vitamin D (1,25 (OH)
1α-hydroxylase. 1,25 (OH)
maintaining calcium homeostasis and acting on osteoblasts, enterocytes,
and the renal tubule. At the renal level, there is another hydroxylase
(24-hydroxylase) which converts 25(OH)D into the inactive form,
24.25-dihydroxyvitaminD [24.25(OH)D]. (Copyright EDISES 2021.
Reproduced with permission)
-D performs numerous functions, including
2
D), by the enzyme
2
Although intestinal phosphorus absorption is very efcient, the organ most involved in its metabolism is the kidney. 85–90% phosphorus ltered at the glomerulus is
reabsorbed in the proximal and distal tubules. Proximal reabsorption of phosphorus is sodium-dependent and increases
under decreased dietary intake; as mentioned above, PTH
induces inhibition of this reabsorption with a nal effect of
urinary excretion of the element. Decreased dietary phosphorus intake results in increased phosphorus clearance.
Hypercalcemia
The clinical laboratory nding of increased serum calcium
values, sometimes accompanied by hypophosphoremia, may
be detected in asymptomatic individuals as an expression of
chronic (hyperparathyroidism) or subtle (neoplasm) disease.
Alternatively, it may be occasional. Clinically manifest
hypercalcemias account for approximately 50% of cases of
hypercalcemia and may present with a wide variety of signs
and symptoms, including recurrent nephrolithiasis, peptic
ulcers, and hypertension.
The etiologic classication of hypercalcemias distinguishes them macroscopically into parathyroid and extraparathyroid. Table 25.12 describes the main causes of
hypercalcemia. Although these are numerous, most hypercalcemic syndromes depend on hyperparathyroidism and
neoplasms. Forms caused by primary hyperparathyroidism
(solitary adenomas of a gland) are often asymptomatic and
have a benign course. In the forms resulting from neoplasia,
this is rarely occult and the laboratory nding is included in
the investigations.
In the presence of hypercalcemia (and altered calcemic
values in general), it is crucial to ascertain that this is true
and does not depend on an alteration of the plasma proteins
(albumin). This is followed by the PTH measurement to
assess the functionality of the parathyroids and the presence
of hyperparathyroidism; the determination of 25-(OH)vitamin D3, and possibly of calcitriol, is recommended in the
presence of PTH values within the reference values.
Figure 25.16 describes the diagnostic algorithm for
hypercalcemia.
344
Ca
()
=×
()
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M. Ciaccio et al.
Table 25.12
Parathyroid
Idiopathic hyperparathyroidism
-Solitary adenoma
-Associated with MEN1 and MEN2
Lithium
Familial hypocalciuric hypercalcemia
Extra-parathyroid
Paraneoplastic hypercalcemia
-Solid malignancies with metastases (breast cancer)
- Solid neoplasms with humoral cause of hypercalcemia (lung and
-Hematological neoplasms
Vitamin D-related hypercalcemia
-Vitamin D intoxication
-Sarcoidosis and other granulomatous diseases
Endocrinopathies (hyperthyroidism)
Iatrogenic
Other
-Milk-alkali syndrome
-Aluminum intoxication
MEN multiple endocrine neoplasms
Fig. 25.16 Diagnostic algorithm of hypercalcemia. (Copyright
EDISES 2021. Reproduced with permission)
Causes of hypercalcemia
kidney cancer)
Normal
PTH
Normal
25-(OH)-Vitamin D
Normal
1,25-(OH)2-Vitamin D
High
Hypercalcemia
Albumin
Increased
High
3
3
Sarcoidosis
Low
Hyperparathyroidism
Vitamin D
intoxication
Normal Cancer
Treatment of hypercalcemia is etiologic.
Hypocalcemia
Hypocalcemia is a less frequent clinical syndrome than
hypercalcemia, characterized by decreased serum calcium
levels, and often accompanied by hyperphosphatemia. The
main causes of hypocalcemia are shown in Table25.13.
A distinction is made between an acute and a chronic
form of hypocalcemia. In the rst one, the clinical relevance
Table 25.13
Hypoparathyroidism
-Idiopathic
-Iatrogenic/surgical
-Familiar
-Functional (due to hypomagnesemia)
Resistance to PTH
-Pseudohypoparathyroidism type 1 and 2
-Alcohol
Vitamin D3 deciency
-Malabsorption
-Chronic kidney disease
Vitamin D3 resistance
Drugs
Other causes
-Acute pancreatitis
-Hyperphosphatemia
-Blood transfusions
PTH parathyroid hormone
Causes of hypocalcemia
of the symptomatology varies according to the entity of
hypocalcemia; indeed, mild hypocalcemia manifests with
asthenia, paresthesias, cramps, and irritability, whereas
severe hypocalcemia determines tetany and muscle spasms.
Acute drug-induced forms are often transient and asymptomatic. On the contrary, chronic forms are characterized by
striking symptoms, including neuromuscular signs, behavioral alterations, parkinsonian symptoms, and basal
gangliacalcications.
Again, albumin should be determined to ascertain hypocalcemia’s nature (true or false). In true hypocalcemia, renal
function assessment is recommended to exclude losses secondary to chronic renal failure. Magnesium also enters the
diagnostic algorithm for hypocalcemia, hypomagnesemia
being invariably associated with hypocalcemia. If magnesium levels are in the normal range, evaluation of PTH, phosphate, and vitamin D
levels, both the depot form and the
3
biologically active form [25-(OH)-D3 and 1,25-(OH)2-D3,
respectively], is performed. In particular, the 1,25-(OH)-D3
assay allows differential diagnosis between vitamin D3resistant and -dependent forms of rickets. The diagnostic
algorithm for hypocalcemias is illustrated in Fig.25.17.
In the presence of albuminemia <4g/dL, it is necessary to
correct calcemia, increasing its value of 0.8mg/dL for each
gram of albumin below the reference value, according to the
formula:
lcemia correct albuminemia
calcemia measured
+
08 4,
Treatment of hypocalcemia is based on the administration
of calcium and vitamin D3 per os.
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345
Fig. 25.17 Diagnostic
algorithm of hypocalcemia.
(Copyright EDISES 2021.
Reproduced with permission)
Normal
Renal function
Normal
Magnesium
Normal
PTH
High
Phosphates
Low
25-(OH)-vitamin D
Hypocalcemia
Albumin
Altered
Low
Low or Normal
High
3
Pseudohypoparathyroidism
Low
Low
Kidney injury
Hypomagnesemia
Hypoparathyroidism
Deficit vitamin D
3
Normal or high
1,25-(OH)2-vitamin D
Normal or high
Vitamin D3-resistant rickets
Metastasis
Pancreatitis
Laboratory Investigations
Calcemia
Total calcemia is determined by colorimetric methods, which
provide accurate and reproducible performance under wellcontrolled operating conditions; the assay does not require
fasting or preparation for testing. However, if the patient is
taking drugs that may interfere with calcemia values (vitamin
D3, lithium), it is advisable to suspend their administration
before performing the assay temporarily. In the presence of
hypoalbuminemia, the above formula is required to obtain the
corrected calcemia. Ionized calcium should be determined in
selected cases (malabsorption, chronic disabling diseases).
Albumin
It is measured by separative methods (serum protein electrophoresis) or techniques that directly evaluate the concentrations, using specific reagents (methods using dyes;
3
Low
Vitamin D3-dependent rickets
fluorimetric methods). Serum protein electrophoresis is
the most reliable among the separative methods. The
albumin assay does not require test preparation or
fasting.
Renal Function
Creatinine measurement and clearance are used to assess
kidney function.
Magnesium
It can be performed by atomic absorption spectrophotometry
or colorimetric enzymatic methods, which are widely used in
clinical practice. The reference values of plasma magnesium
are 1.7–2.1mg/dL.
Phosphate
It is performed by colorimetric enzymatic techniques and
requires fasting from the previous 12hours.
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Medullary
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Table 25.14 Values of 25–(OH)-vitamin D3 and their interpretation
Values of 25–(OH)-vitamin D3 (ng/mL) Interpretation
<20 Deciency
20–29 Insufciency
30–100 Sufciency
>150 Toxicity
Serum or plasma should be separated as soon as possible
from the corpusculate, which is very rich in phosphate esters.
The reference values of plasma phosphates are 2.5–4.5mg/
dL. Phosphaturia in 24-hour urine is of little value if not
related to dietary intake and tubular reabsorption; therefore,
phosphate clearance, corrected with creatinine clearance
(400–1000mg/24h), is more frequently calculated.
PTH
PTH determination is a diriment test in the etiologic diagnosis of hypercalcemia (for the differential diagnosis between
PTH-dependent and non-PTH-related forms) and the differential diagnosis between hypoparathyroidism and pseudohypoparathyroidism. PTH is determined by immune
chemiluminescence; the fragment tested is PTH 1-84, or
intact PTH.Reference values are between 10–55pg/mL.
Vitamin D
3
The most commonly assayed vitamin D3 metabolite is
25-(OH)-vitamin D3, which indicates available stores related
to dietary intake and synthesized from the skin. It is appropriate to measure1,25-(OH)2-vitamin D3 for the differential
diagnosis of vitamin D3-dependent and vitamin D3resistant rickets. Reference values of 25-(OH)-vitamin D3
are shown in Table25.14. The reference values of 1,25-(OH)2vitamin D3 are: 20–60pg/mL.
PTHrP
It is performed when a neoplastic origin of hypercalcemia is
suspected. Values below 1pmol/L are suggestive of tumor
etiology. The PTHrP assay has limited uptake in clinical
practice.
Adrenal Gland
MarcelloCiaccio, LuisaAgnello, and GiuliaBivona
Anatomy
The adrenal gland is an organ located retroperitoneally
suprarenal. The cortical zone constitutes approximately 90%
of the gland and surrounds the medullary (Fig.25.18). In the
cortical, we distinguish three histologically different zones:
glomerular, fasciculate, and reticular, each deputed to syn-
M. Ciaccio et al.
Left adrenal
gland
Left
kidney
Fig. 25.18 Adrenal glands. (Copyright EDISES 2021. Reproduced
with permission)
Right adrenal
gland
Cortical
Right
kidney
thesizing a different steroid hormone. Numerous small arteries serve the adrenal gland from the inferior phrenic and
renal arteries. The venous outow is ensured by a single vein
that ows on the right into the inferior cava and, on the left,
into the renal.
Embryologically, the cortical is mesodermal (gonadal
crest sketch) derived, and the medullary ectodermal (neural
crest) derived.
Adrenal Cortical Hormones
Biochemistry andTransport
Adrenal steroids share cyclopentanoperhydrophenanthrene
in their chemical structure and may contain 19 or 21 carbon
atoms. Hormones with 19 carbon atoms (C19) have androgenic activity and may have a ketone group at position 17
(17-ketosteroids). Steroids with 21 atoms (C21) regulate
intermediate metabolism (glucocorticoids) or sodium
homeostasis (mineralocorticoids).
Dehydroepiandrostenedione (DHEA) represents the primary adrenal androgen, cortisol among the glucocorticoids,
and, nally, aldosterone among the mineralocorticoids.
The precursor of steroid hormones is cholesterol; it is
taken up by adrenal cortical cellsvia the combined ApoB100/ ApoE ligand on low-density lipoprotein (LDL). The
synthesis of all adrenal steroids begins with transforming
cholesterol into a common precursor, pregnenolone. Most of
the biosynthetic steps of steroidogenesis are catalyzed by
enzymes belonging to the supergene family of cytochrome
P450 oxidases (Fig.25.19).
The specicity of synthesis in the variousadrenocortical
zones depends on specic receptors for ACTH and on the
distribution of specic enzyme systems. Indeed, cells in the
glomerular zone, which lack 17α-hydroxylase, do not participate in the synthesis of cortisol and androgens, for which
Cholesterol
Pregnenolone
Corticosterone
DHEA-S
stosterone
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25 Endocrine System
17-OH-
pregnenolone
Progesterone
DOC
Aldosterone
Fig. 25.19 Adrenal steroidogenesis. (Copyright EDISES 2021.
Reproduced with permission)
17-OH-
progesterone
11-
Desoxycortisol
Cortisol
DHEA
Te
Oestron
18-aldehydesynthetase
17.20-desmolase
Aromatase
17Ketosteroid reductase
Estradiol
this enzyme is essential. In contrast, the fasciculate and reticular zonecells, not possessing the 18-hydroxylase enzyme,
cannot synthesize aldosterone. However, cells in the three
zones can synthesize deoxycorticosterone, as the initial steps
are common to both enzymatic pathways.
Almost all testosterone and cortisol (98%) circulate
bound to plasma proteins, while only 60–65% of aldosterone
circulates bound to nonspecic plasma proteins (15–20%
corticosteroid-binding globulin [Corticosteroid-Binding
Globulin, CBG] and 40–50% albumin). Testosterone binds
with high afnity to sex hormone–binding globulin (SHBG)
and low afnity to albumin. The transport protein with a
higher binding afnity for cortisol is cortisol-binding globulin (CBG), an α-globulin that can bind up to 25 μg/dL of
circulating hormone. When plasma cortisol concentrations
exceed this concentration, the excess is distributed partly by
binding to albumin and partly by increasing the free
fraction.
Metabolism
The daily cortisol secretion is about 25–30mg (8–10mg/m2)
and follows a circadian rhythm, peaking in the rst hours
after waking up and decreasing during the day until reaching
its lowest point at night. Cortisol metabolism strictly depends
on the activity of the enzyme 11β- hydroxysteroidodehydrog
enase (11β-HSD), of which two isoforms are known:
11β- HSD- 1 and 11β-HSD-2. The rst is liver-based and converts cortisone into cortisol (active corticosteroid); the second mediates the reverse transformation in the kidney and
other tissues. At the hepatic level, cortisol and cortisone are
conjugated with glucuronic acid (95%) or sulfuric acid and
subsequently excreted renally.
347
A small portion of the cortisol produced (up to about
150μg per day) is excreted and representscirculating cortisol in free form, ltered out by the kidney (urinary free
cortisol).
The average daily aldosterone secretion is 100–200μg/
day, of which 30% is in free form, and 70% binds weakly to
plasma transport proteins, CBG, and albumin.
Metabolism of aldosterone is characterized by an initial
hepatic passage that considerably reduces its concentration
(≈75%), followed by renal excretion; under adequate dietary
salt intake, daily excretion of the hormone is approximately
50–250μg.
Adrenal androgens are secreted as DHEA and its ester
with phosphate (DHEA-S), 15–30 mg/day. The adrenal
gland also secretes small amounts of androstenedione,
11β-hydroxyandrostenedione, and testosterone, from which
the female urinary 17-ketosteroids originate. About onethird of them, in the male, is of testicular origin.
Glucocorticoid (GR) and steroid (MR) receptors are intracellular, and hormone binding activates or inhibits transcription factors. While GR binds only corticosteroids, MR binds
both with equal afnity. Alterations in GR result in glucocorticoid resistance syndromes characterized by silent
hypercortisolism.
Physiology
The synthesis and secretion of glucocorticoids and mineralocorticoids occur in very different homeostatic contexts.
Cortisol secretion is an expression of the control exerted on
the adrenal gland by the hypothalamic-pituitary endocrine
axis; aldosterone, on the other hand, is secreted in response
to the stimulus of angiotensin II, a potent vasoconstrictor
regulated by the renin-angiotensin system.
Glucocorticoids
Plasma cortisol is secreted in response to pituitary corticotropin (ACTH) stimulation, which, in turn, responds to stimulation by the hypothalamic release factor (CRH). This
mechanism of regulation of the endocrine axis is dened as
positive feedback and is common to all the glands under
hypothalamic-pituitary control. The inhibition by plasma cortisol on ACTH and CRH represents negative feedback. The
resultant integration of these inhibition or release stimuli by
each glandular product represents the basis for the foundation
of the hypothalamic-pituitary-target gland endocrine axis.
However, numerous other factors are involved in modulating
these feedbacks, such as stress and hypoglycemia (Fig.25.20).
Cortisol exerts negative feedback on ACTH in two ways:
rapid, entrusted to GR, and delayed, due to suppressing synthesis of the precursor, pro-oppiomelanocortin (POMC).
POMC is also a precursor of melanocyte-stimulating hormone (MSH) and endogenous opioids (met-enkephalins and
β-endorphins).
348
Stress, hypoglycemia, hypotension,
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Circadian rhythm
Hypothalamus
Vasopressin
cytokines
Positive feedback
Negative feedback
Fig. 25.20 Regulation of cortisol secretion. (Copyright EDISES 2021.
Reproduced with permission)
y
Adenohypophysis
Adrenocortical
Cortisol
surgery, fever
CRH
ACTH
It is helpful to remember that CRH also exerts a feedback
control on the sympathetic nervous system, stimulating the
locus coeruleus and inhibiting this activation by plasma
cortisol.
Mineralocorticoids
Aldosterone secretion is regulated primarily by activation of
the renin-angiotensin system. Renin, a hormone produced
and secreted by the juxtaglomerular cells surrounding the
glomerulus’s afferent arteriole, mediates the circulation of
angiotensinogen, produced in the liver, into angiotensin I,
which becomes angiotensin II by the angiotensin-converting
enzyme (ACE). Angiotensin II is a potent arteriolar vasoconstrictor that stimulates the biosynthesis and release of aldosterone from cells in the glomerular zone of the corticosurrene.
Aldosterone secretion also follows a circadian rhythm, similar to that of cortisol.
Aldosterone regulates extracellular volume by inducing
changes in renal hemodynamics and tubular sodium reabsorption. In addition to hypovolemia, other stimuli to renin
secretion are activation of sodium load-sensitive macula
densa chemoreceptors, orthostatism, and atrial natriuretic
peptides. Intrarenal pressure and sodium load sensors
increase renin secretion; natriuretic peptides reduce it.
Although to a lesser extent, potassium levels and ACTH
are also involved in regulating aldosterone secretion.
Biological Actions
Glucocorticoids
The biological roles of cortisol are numerous and occur at
various levels. Cortisol intervenes in the metabolism of glycides, lipids, and proteins by inducing hyperglycemia and
stimulating protein and lipid catabolism. Besides exerting
these counter-insular effects, cortisol can inhibit insulin synthesis. In addition, cortisol has numerous immunomodulatory effects, mainly through two mechanisms: reduction of
the secretion of inammatory cytokines and regulation of
capillary permeability. Cortisol also controls the regulation
of extracellular uid by suppressing the secretion of vasopressin and inhibiting waterentry into cells. Finally, cortisol
is secreted in response to stressogenic stimuli of various
kinds: surgery, trauma, exercise, mood deections, anxiety,
hypoglycemia, and fever.
Mineralocorticoids
A genomic mechanism mediates the regulatory action of
mineralocorticoids on extracellular volume through binding
to the MR receptor on the epithelial cells of the target organs.
In particular, at the level of the renal cortical collecting ducts,
sodium enters passively in favor of an electrochemical gradient through special channels; subsequently, it is actively
excreted by the ATP-dependent Na
+-K+
pump. Aldosterone
acts directly on the transcription of genes encoding for
sodium channels and the sodium pump, thereby promoting
the reabsorption of sodium and water (water is passively
reabsorbed along with sodium) and increasing the excretion
of potassium and hydrogen ions. In addition, the hormone
stimulates sodium reabsorption in the sweat, salivary and
gastrointestinal glands. This increases blood volume and,
consequently, blood pressure.
Androgens
Androgens promote the development of secondary sexual
characteristics in men and are responsible for virilization in
women. Adrenal forms have little effect in men, where
gonadal androgens primarly control the reproductive function. Furthermore, the androgenic activity of DHEA,
DHEA-S, and 11β-hydroxyandrostenedione issignicantly
reduced compared to testosterone. Adrenal androgens are
under the control of ACTH.
Hypocorticosurrenalism
Hypocorticosurrenalism, or adrenal insufciency, is characterized by the reduced or absent function of the adrenal cortex, either due to the inability of the adrenal to produce
sufcient amounts of hormones (primary hypocorticosurrenalism) or secondary to hypothalamic-pituitary pathologies
associated with impaired ACTH production or secretion
(secondary hypocorticosurrenalism) (Table25.15).
Primitive hypocorticosurrenalism is divided into an acute
form, which represents a clinical emergency with the manifestations typical of hypovolemic shock, and a chronic form,
known as Addison’s disease, which is the result of progressive destruction of the adrenal gland characterized by asthenia, which is the most frequent symptom, weight loss, arterial
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349
Table 25.15 Classication of adrenal insufciency
Primitive
Organic forms
-Autoimmune
-Infectious (tuberculosis, mycosis, viral infections)
-Hemorrhagic
-Inltrative
-Invasive
Iatrogenic forms
-Surgery (removal)
- Enzyme inhibitor therapy (metopyrone, ketoconazole,
aminoglutethimide)
-Therapy with cytotoxic agents (mitotane)
Congenital forms
-Congenital deciencies of adrenal steroidogenesis
-Familial glucocorticoid deciency
-Congenital adrenal hypoplasia
-Adrenoleukodystrophy
Secondary
Organic forms
-Hypothalamic-pituitary disease
- Inhibition of the HPA axis after removal of glucocorticoidsecreting tumors
Iatrogenic forms
-Glucocorticoid therapy
HPA hypothalamic pituitary adrenal axis
hypotension, hypoglycemia, anemia, depression and hyperpigmentation of the skin. In this case, recognizing the disease in the early stages may not be easy because the signs
and symptoms only manifest when more than 90% of the
glands are destroyed. Primary adrenal insufciency is relatively rare, with a higher incidence in subjects aged between
30 and 40years. In the majority of cases (80–90%), it is due
to autoimmune destruction of the glands, characterized by
progressive degenerative atrophy of the cortical adrenal,
with diffuse cytotoxic T lymphocyte inltration, withoutchanges in the medullary area; less frequently (10%), it
is due to tuberculosis and, rarely (1%), other conditions are
found (Table25.15). Anti-adrenal antibodies are present in
most affected patients, although their role is not yet fully
understood. In addition, some patients have antibodies
directed against other endocrine glands. In about half of the
cases, Addison’s disease is a component of polyglandular
autoimmune syndromes (PAS) along with other autoimmune
endocrinopathies such as hypogonadism, Hashimoto’s thyroiditis, vitiligo, hypoparathyroidism, pernicious anemia,
and celiac disease.
Hypercorticosurrenalism
The term hypercorticosurrenalism refers to a condition characterized by single or combined hypersecretion of hormones
produced by the cortical adrenal gland. In particular, cortisol
excess causes Cushing’s syndrome, and aldosterone
excesscauses hyperaldosteronism.
Cushing’s Syndrome
It is a rare disease caused by chronic exposure to cortisolexcess due to endogenous (pituitary or extrahypophyseal
tumors) and exogenous (chronic corticosteroid treatment)
causes. All endogenous forms are characterized by increased
cortisol production by the adrenals and can be distinguished
into ACTH-dependent and ACTH-independent forms
(Table25.16). Cushing’s disease is the most commonamong
the ACTH-dependent forms. Cushing’s disease is characterized by an increased secretion of ACTH, which in 90% of
cases is due to a pituitary adenoma and only in 10% of cases
to hyperplasia of ACTH-secreting cells; the latter may be the
consequence of alterations in the central nervous system
leading to excessive hypothalamic production of CRH or
CRH-secreting intrasellar gangliocytomas.
ACTH-dependent forms are rarely due to ectopic secretion of ACTH or CRH from non-pituitary tumors; among
these, the most common are small cell lung carcinoma or
thymic, pancreatic, or ovarian carcinoid tumors, medullary
thyroid carcinoma or bronchial adenomas. Endogenous
ACTH-independent forms are, instead, due to adrenal
neoplasms, usually unilateral and, in about half of the cases,
malignant. Bilateral adrenal hyperplasias are characterized
by a nodule with a diameter >1cm (macronodular) or <1cm
(micronodular) and may be due to a hereditary disease
(micronodular pigmented dysplasia) or to the stimulation of
cortisol secretion by gastric inhibitory peptide (GIP) or
luteinizing hormone, associated with the expression of specic receptors for these hormones in the adrenal cortex.
The most common cause of Cushing’s syndrome is the
administration of exogenous corticosteroids or ACTH for
therapeutic purposes.
The clinical signs of Cushing’s syndrome are variable due
to the amount and duration of excess cortisol. In severe cases
of hypercortisolism, the signs and symptoms are unmistakable. They include muscle weakness and easy fatigability
due to hypotrophy of the skeletal musculature, striae rubrae,
Table 25.16
ACTH-dependent
(70–80%)
ACTH-independent
(20–30%)
ACTH adrenocorticotropic hormone, CRH corticotropin-releasing
hormone
Endogenous causes of Cushing’s syndrome
Causes Percentage
Cushing’s disease
ACTH ectopic secretion
syndrome
CRH ectopic secretion syndrome
Unilateral adrenal adenoma
Unilateral adrenal carcinoma
Bilateral macronodular adrenal
hyperplasia
Bilateral micronodular adrenal
hyperplasia
60–70
5–10
Very rare
10–22
5.7
<2
<2
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M. Ciaccio et al.
especially in the abdomen, facial plethora, and centripetal
obesity due to deposition of fatty tissue in the upper part of
the face leading to the appearance of the typical full moon
face, in the interscapular region with buffalo hump, in the
supraclavicular area, and the abdomen. Other non-specic
symptoms of Cushing’s syndrome are osteoporosis, hirsutism, acne, hypertension, complicated in some cases by
edema and heart failure, amenorrhea in women, and impotence in men. In addition, patients often present with emotional disturbances or psychosis (irritation, difculty in
concentrating, memory loss, and depression). It should be
remembered that there are cyclical forms of the disease in
which hormone overproduction occurs only periodically.
This is because many conditions such as obesity, chronic
alcoholism, pregnancy, chronic exercise, anorexia nervosa,
and depression can clinically mimic Cushing’s syndrome
with increased cortisolemia. This condition can be treated by
correcting the underlying pathology.
Hyperaldosteronism
It is a syndrome characterized by an inappropriately high
production of aldosterone that may be due to increased and
autonomous production of the hormone in the adrenal cortex
(primary hyperaldosteronism) or to non-pituitary and extrasurrenal stimuli with consequent hypersecretion of aldosterone (secondary hyperaldosteronism). Hypersecretion of
aldosterone induces reabsorption of sodium ions leading to
water retention, expansion of extracellular volume, and
hypertension. It also causes increased excretion of potassium
and hydrogen ions which may lead to hypokalemia (observed
in 30–50% of cases) and metabolic alkalosis.
Primary hyperaldosteronism is characterized by hypersecretion of aldosterone, independent of activation of the
renin- angiotensin system, which may be due to a unilateral
aldosterone-secreting adrenal adenoma, known as Conn syndrome, (35%) or bilateral adrenal hyperplasia, also known as
idiopathic hyperaldosteronism (65%). Other rarer causes are
unilateral adrenal hyperplasia (2%), adrenal carcinoma
(<1%), ectopic aldosterone-secreting tumors (ovarian and
renal tumors), and familial hyperaldosteronism, of which
three different forms are known (<2%). Familial type I
hyperaldosteronism, or glucocorticoid-sensitive aldosteronism (GRA), is very rare (<1%) and has an autosomal dominant transmission; it is due to the fusion of the promoter
region of the CYP11B1 gene, which codes for
11β-hydroxylase, and the coding sequences of the CYP11B2
gene, which codes for the aldosterone-synthetase enzyme,
leading to the formation of the CYP11B1/CYP11B2 chimera
gene. This form is characterized by ACTH-dependent aldosterone hypersecretion and elevated levels of the “hybrid”
steroids 18-oxocortisol and 18-hydroxycortisol, which are
under the control of ACTH.According to some authors, chil-
dren or young adults with severe or resistant hypertension
and a positive family history of early hypertension and/or
premature hemorrhagic stroke are highly likely to be affected
by GRA.In familial hyperaldosteronism type II, which also
has autosomal dominant transmission, the underlying gene
defect is not yet known; recent studies have identied an
association with the chromosome 7:7p22 region. It represents the familial form of aldosterone-secreting adenoma
and bilateral adrenal hyperplasia. Unlike GRA, type II
hyperaldosteronism is not glucocorticoid-sensitive nor clinically distinguishable from the nonfamilial forms of primary
hyperaldosteronism. Finally, familial type III hyperaldosteronism is due to mutations in the KCNJ5 gene, which
encodes for the potassium channel and results in increased
sodium conductance and cellular depolarization, with subsequent voltage-dependent calcium channel opening resulting
in increased aldosterone production.
From a clinical point of view, hypertension isthe main,
and in most cases only, clinicalsign.
Secondary hyperaldosteronism is characterized by
increased aldosterone production in response to activation of
the renin-angiotensin system. It may be associated with the
accelerated phase of hypertension due to increased renin
secretion, or as a result of a preexisting edematous syndrome
or salt loss, as a compensatory mechanism of reduced volemia or cardiac output to maintain blood pressure within normal values (Table 25.17). In addition, during pregnancy,
secondary hyperaldosteronism is physiologically observed
due to estrogens inducing an increase in renin levels and
plasma renin activity (PRA).
Laboratory Investigations
The diagnostic suspicion of corticosurrenal disorders is
based on a careful personal and family history and a careful
physical examination. Laboratory testsand imaging play a
central role in conrming the diagnostic hypothesis.
In particular, laboratory investigations include plasma
and urinary assays of hormones and their metabolites, both
under basal conditions and following stimulation or
inhibition.
Table 25.17 Secondary hyperaldosteronismcauses
With arterial hypertension
-Renovascular hypertension
-Reninoma
-Malignant hypertension
-Essential hypertension with high renin
Without arterial hypertension
- Edema syndromes: liver cirrhosis, nephrotic syndrome, protein
deciency, heart failure, etc.
- Loss of salts: vomiting, diarrhea, abuse of diuretics, shock,
nephropathies
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351
Basal Measurements
Blood
Cortisol
Ninety percent of cortisol in the blood circulates bound to
proteins, and the remaining 10% is free; therefore, the evaluation of cortisolemia is inuenced by the concentrations of
its transport proteins (CBG and albumin); alterations of the
transport proteins, both physiological (pregnancy) and pathological (infections in the acute phase, hepatic cirrhosis,
nephrotic syndrome) can determine false cortisolemia values. In these cases, the free cortisol index is calculated rather
than evaluating the total cortisolemia. This involves the evaluation of the ratio between total serum cortisol and
CBG. Other formulas are available that consider not only
CBG but also albumin. However, they are not yet used in
clinical practice. Moreover, since cortisol has a circadian
secretion, it is necessary to dene the sampling time; it is
generally performed between 8 and 9a.m., when hormoneconcentration reaches its peak.
In normal subjects, serum cortisol concentrations are
highest in the early morning (approximately 6:00 a.m.),
ranging from 10 to 20μg/dL.Serum cortisol concentrations
range from 3 to 10μg/dL at 4:00 p.m.; concentrations are
lowest, less than 5 μg/dL, one hour after the usual sleep
period.
Potassium
To increase the diagnostic accuracy of plasma potassium levels, increase the dietary sodium intake (2–3g/day for at least
5days) to identify latent hypokalemia. In addition, diuretic
therapy or therapy with ACE inhibitors should be suspended
for at least 3 weeks because it may give false positives.
Normal potassium values are 3.5–4.5mEq/L.
Aldosterone andRenin
Due to the circadian nature of aldosterone secretion, a single blood collection is not sufcient for measuring aldosterone and renin. In addition, aldosterone levels vary with
body position (they increase with standing) and diet (with
excessive potassium intake). Therefore, the patient should
maintain the standing or supine position for at least
15–30 minutes before blood sampling. Normal plasma
aldosterone values are 5–10ng/dL in clinostat and <20ng/
dL in orthostatic.
Two techniques exist for determining renin: measurement
of plasma renin activity (PRA) and direct plasma renin assay.
PRA is based on the principle that renin mediates the activation of angiotensinogen to angiotensin I and is performed as
follows:
1. Prepare two tubes with the same amount of plasma to be
tested for PRA.
2. The two tubes are incubated for one hour but at different
temperatures: the rst at 37 °C and the second at 4 °C.
3. At the end of the incubation, measure the amount of
angiotensin I present in the two tubes. The PRA is thedifference between the amount of angiotensin I measured in
the rst tube and the amount of angiotensin I measured in
the second tube.
Values are expressed as angiotensin I (in ng) produced per
mL of solution in one hour. In patients with optimal sodium
intake (2g/day), normal PRA values are 0.5–2.5ng/mL/h in
clinostat and 2–4 ng/mL/h in orthostatic. This is the most
Alternatively, the concentration of active renin, which has
less inter-laboratory variability than PRA, can be measured
directly in plasma. However, renin is labile, so special care
must be taken when preparing the sample; blood must be
collected in a pre-cooled tube, the sample must be centrifuged at 4 °C, and then the plasma quickly separated and
frozen at −20°C until the assay is performed.
In either case, sampling should be performed in the orthostatic position (standing for at least two hours prior to sampling) or in the clinostat position (supine for at least two
hours prior to sampling).
ACTH
Basal ACTH secretion shows a circadian rhythm with lower
levels in the evening. Sampling for measurement of plasma
levels should be performed in the morning, between 8 and
10 a.m. The ACTH assay is important in adrenal insufciency because it allows differential diagnosis between primary and secondary forms.
DHEA Sulfate
It is secreted primarily by the adrenals and only in small
amounts by the gonads. Thus, DHEA sulfate is a helpful
indicator of adrenal androgen secretion.
Urinary Measurements
Free Cortisol
Measurement of free urinary cortisol is helpful in the assessment of adrenal function. Since free cortisol is ltered at the
glomerular level and excreted by the kidney, the cortisol measurement in the 24-hour urine represents the free portion of
serum cortisol and, at the same time, its “integrated” measurement, unaffected by variations due to the circadian rhythm.
Immunometric methods perform the assay. One of the main
limitations of the assay is the inadequacy of the 24-hour urine
collection. It is, therefore, advisable to perform the urine creatinine measurement to verify the validity of the collection.
Since cortisol secretion is subject to daily uctuations, collecting 24-hour urine for 2–3days is recommended.
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