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23 Biomarkers ofStroke
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PARK7
after the symptomsonset. It does not allow the differential
diagnosis between ischemic and hemorrhagic stroke, or
PARK7 has a reparative role in neurological damage in oxidative stress processes; its levels increase during stroke, with
a peak between 30min and 3h after the symptomsonset. It
does not allow making a differential diagnosis between ischemic and hemorrhagic stroke or TIA.
TIA.
Table 23.4 shows the potential clinical applications of
biomarkers at various stages of the disease, from risk prediction to diagnosis, differential diagnosis, and prognosis.
Given the high heterogeneity of stroke, a single biomarker
may not be sufcient to capture the different aspects of
stroke pathogenesis. Therefore, a multi-marker strategy that
NDKA
assesses the various stroke-related molecular alterations may
be necessary. Translating stroke biomarkers into clinical
NDKA is an enzymatic protein of neurons whose levels
increase during stroke, with a peak between 30min and 3h
Table 23.4 Potential clinical application of stroke biomarkers
Type Biomarker Biological function
Risk Lp-PLA2
Oxidized LDL Modied (oxidized) form of LDLs involved in the development of atherosclerotic plaque
HDL
MR-proADM Peptide with vasodilatory activity
ADMA Endogenous inhibitor of nitric oxide synthetase; it is released by endothelial cells and
SDMA Structural isomer of ADMA
CRP Acute-phase protein involved in the inammatory response and innate immunity
NT-proBNP Neurohormone secreted by the myocardium with natriuretic, diuretic, and vasodilatory
hsTnT Biomarker of myocardial necrosis. It is a diagnostic biomarker of acute myocardial
F2-isoprostanes Oxidative degradation products of arachidonic acid
Diagnosis Glutamate Neurotransmitter amino acid that activates cell surface receptors on the membranes of
S100-β
VWF Plasma glycoprotein involved in platelet adhesion
MMP-9 Calcium-dependent proteolytic enzyme involved in the degradation of the basal lamina and
MCP-1 Chemokine, which regulates the migration and inltration of monocytes and macrophages
VCAM-1 Transmembrane protein involved in endothelial cell–leukocyte signal transduction
NT-proBNP Neurohormone with natriuretic, diuretic, and vasodilatory activity
CRP Acute-phase protein involved in the inammatory response and innate immunity
D-dimer Fibrin degradation product; it reects a global activation of coagulation and brinolysis
Differential diagnosis:
ischemic stroke
Differential diagnosis:
hemorrhagic
transformation
ADMA asymmetric dimethylarginine, cFN cellular bronectin, HDL high-density lipoprotein, hsTNT high-sensitivity troponin T, LDL
lipoprotein, Lp-PLA2 lipoprotein-associated phospholipase A2, MCP-1 monocyte chemoattractant protein, MMP matrix metalloproteinase,
MRproADM midregional proadrenomedullin, PAI-1 type 1 inhibitor of plasminogen activator, CRP C-reactive protein, SDMA symmetric dimethyl-
arginine, TAFI thrombin-activated brinolysis inhibitor, VCAM-1 vascular cell adhesion protein, VWF von Willebrand factor
S100-β
cFN Main component of the extracellular matrix involved in the processes of healing and cell
GFAP Monomeric lamentous protein specic to astrocytes, whose levels increase during
PAI-1 Major inhibitor of the brinolytic system
TAFI Enzyme that hydrolyzes the C-terminal bonds of brin to prevent brinolysis and inhibits
cFN Main component of the extracellular matrix involved in the processes of healing and cell
MMP Calcium-dependent proteolytic enzyme involved in the degradation of the basal lamina and
Enzyme that catalyzes the degradation of platelet- activating factor by hydrolysis
Lipoproteins with anti- atherosclerotic, antithrombotic, anti-inammatory, and antioxidant
activity
causes endothelial dysfunction
activity
infarction and a prognostic diagnostic biomarker of ischemic stroke
neurons and glial cells
Homodimer glial protein that regulates intracellular calcium levels; biomarker of blood–
brain barrier dysfunction
the extracellular matrix, leading to the destruction of the blood–brain barrier
Homodimer glial protein that regulates intracellular calcium levels; biomarker of blood–
brain barrier dysfunction
adhesion
ischemic stroke
the activation of brinogen
adhesion
the extracellular matrix, leading to the destruction of the blood–brain barrier
practice is a goal of many researchers, clinicians, and pharmaceutical industries.
low- density
312
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M. Ciaccio and L. Agnello
Recommended Readings
Adams HP Jr, Bendixen BH, Kappelle LJ etal (1993) Classication
of subtype of acute ischemic stroke. Denitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172in Acute Stroke
Treatment. Stroke 24(1):35–41
Johnston SC, Rothwell PM, Nguyen-Huynh MN etal (2007) Validation
and renement of scores to predict very early stroke risk after transient ischaemic attack. Lancet 369(9558):283–292
Maestrini I, Ducroquet A, Moulin S etal (2016) Blood biomarkers in
the early stage of cerebral ischemia. Rev Neurol (Paris) 172(3):198–
219. https://doi.org/10.1016/j.neurol.2016.02.003
Ng GJ, Quek AM, Cheung C etal (2017) Stroke biomarkers in clin-
ical practice: a critical appraisal. Neurochem Int. https://doi.
org/10.1016/j.neuint.2017.01.005. pii: S0197-0186(16)30460-0
SPREAD (2012) Ictus cerebrale: linee guida italiane di prevenzione e
trattamento, VII ed
Thrombophilia
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MarcelloCiaccio
24
Introduction
Thrombophilia screening is essential for recognizing patients
at risk of venous thromboembolism and pulmonary embolism. This chapterdescribes the clinicalconditions at high
risk of thrombophilia andlaboratory test for thrombophilia
screening.
Hereditary andAcquired Causes
ofThrombophilia
Thrombophilia is dened as the predispositionto develop
thrombotic events in the venous and/or arterial district. It
is typically characterized by the onset ofclinical manifestations at a young age (<50years). Although thrombophilia
can be due to congenital and acquired causes, most thrombophilic alterations are congenital. The most frequent clinical manifestation of thrombophilia is deep vein thrombosis
(DVT). This is a multifactorial condition resulting from
the interaction of acquired and congenital risk factors
(Table24.1).
The simultaneous presence of congenital and acquired
risk factors signicantly increases the overall risk of
DVT. Moreover, surgical interventions, pregnancy, puerperium, estroprogestinic therapy, and prolonged immobilization represent transient risk factors.
The prevalence of inherited disorders is variable and
depends on the type of defect. For example, the preva-
M. Ciaccio (*)
Department of Biomedicine, Neurosciences and Advanced
Diagnostics, Institute of Clinical Biochemistry, Clinical Molecular
Medicine and Clinical Laboratory Medicine, University Hospital
“P.Giaccone”, Palermo, Italy
Department of Laboratory Medicine, University Hospital
“P.Giaccone”, Palermo, Italy
e-mail: marcello.ciaccio@unipa.it
Table 24.1
Congenital Acquired
ATIII deciency Pregnancy and puerperium
Protein C deciency Postoperative status
Protein S deciency Immobilization
Factor V Leiden Trauma
Factor II G20210A mutations Elderly
Dysbrinogenemia Estrogen and estroprogestinic therapy
Hyperhomocysteinemia Anti-phospholipid antibody
lence of antithrombin III (ATIII) deciency is around
0.2% in the general population, protein C deciency
around 0.5%, factor V of Leiden (FV Leiden) at 3–7%,
and prothrombin G20210A (FII G20210A) at 5%. Overall,
the incidence of venous thromboembolism remains high
despite the primary and secondary prevention measures
implemented in recent years. Pulmonary embolism, a
dreaded complication of venous thromboembolism, is a
high-mortality condition due to its nonspecic clinical
presentation.
events of the arterial district. However, the usefulness of
screening in these cases and, therefore, the potential therapeutic and clinical implications are still debated.
Congenital and acquired causes of thrombophilia
syndrome
Hyperhomocysteinemia
Thrombophilia can also be associated with thrombotic
Thrombophilia Screening
Thrombophilia screening, based on the search for conditions
predisposing to thrombosis, is an essential diagnostic tool
allowing to identify subjects at high risk of developing a
thrombotic event and to dene the most appropriate treatment for a patient with thrombosis.
The introduction of large-scale genetic testing and the
spread of knowledge about the hereditary factors underlying
thrombophilia led to an exponential increase in requests for
thrombophilia screening in the early 1990s.
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023
M. Ciaccio (ed.), Clinical and Laboratory Medicine Textbook, https://doi.org/10.1007/978-3-031-24958-7_24
313
314
Patient with thromboembolism or positive family history*
FV Leiden FII G20210A
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M. Ciaccio
The laboratory plays a crucial role in thrombophilia
screening by allowing the identication of the nature and
causes of the coagulation disorder.
Indications forPerforming Thrombophilia
Screening
The main indication for thrombophilia screening is evaluatingthe risk of recurrence after the first thromboembolic episode or after recurrences. In addition to
symptomatic subjects, thrombophilic screening should
also be extended to asymptomatic subjects who are firstdegree relatives of hereditary thrombophilia carriersor
have a strong family history of thromboembolic diseases.
Once the overall risk has been defined, the most appropriate anticoagulant therapy can be started. Immediately
after the first thromboembolic event, the risk of recurrence is exceptionally high and remains higher than that
of the general population for a long time. The estimated
incidence of 5%/year supports prolonged secondary anticoagulant prophylaxis. However, the patient’s compliance and the hemorrhagic risk are considered when
choosing prolonged antithrombotic prophylaxis. It should
also be considered that men have a higher risk of recurrence than women.
The indications for performing thrombophilia screening
are:
• Young age of the thrombotic event (<50years)
• Idiopathic thrombosis
• Recurrent thrombosis
• Thrombosis with atypical localization (thrombosis of the
cerebral veins, mesenteric veins, and splanchnic
circulation)
• Skin necrosis due to the use of oral anticoagulants
• Antiphospholipid antibody syndrome
• Neonatal fulminant purpura
• First-degree relatives of subjects with hereditary
thrombophilia
• Poly-abortion
Laboratory Diagnosis
Thrombophilia screening is based on the followingbasic and
specialist tests (Fig. 24.1):
• Prothrombin time (PT)
• Activated partial thromboplastin time (aPTT)
• ATIII (functional method)
FV Leiden FII G20210A
Heterozygous, homozygous
or double heterozygous
Hereditary factors
Protein CProtein SATIII Fibrinogen
Reduced on at least two occasions
Protein S
Ag
Protein C
Ag
Reduced
Congenital inhibitor deficiency
Fibrinogen
Ag
ATIII
Ag
Normal
Dysfibrinogenemia
No
Rule out
thrombophilia
Ab anti-β2-glycoprotein 1
LAC
Positive on at least two occasions
Acquired factors
IgG/IgM
Antiphospholipid
antibody syndrome
Ab anti-cardiolipin
IgG/IgM
No
Rule out
thrombophilia
Hybrid forms
FVIII and
Homocysteine
Increased
Rule out transitory
causes
Ye s
Hyperhomocysteinemia
Increased Factor VIII
Fig. 24.1 Diagnostic algorithm of thrombophilia. Ag antigen, ATIII antithrombin III, LAC lupus anticoagulant. (Copyright EDISES 2021.
Reproduced with permission)
24 Thrombophilia
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• Protein C (functional test)
• S protein (functional test)
• Fibrinogen (Clauss method)
• Lupus anticoagulant (LAC)
• Anti-beta-2-glycoprotein-1 antibodies
• Anti-cardiolipin antibodies
• Factor VIII
• Homocysteinemia
• Genetic testing for FV Leiden and FII G20210A.
PT and aPTT are rst-level tests that allow identifying a
coagulative imbalance. In the case of positivity, the functional tests for ATIII, protein C, and protein S must be conrmed by the antigenic method based on the specic
protein’s measurement. In order to diagnose one of these
defects, it is also essential to exclude clinical conditions clinical conditions associated with reduced levels
ofphysiological inhibitors (e.g., hepatopathy, therapy with
oral anticoagulants or heparin, intake of estroprogestin,
pregnancy). Thus, it is advisable to also perform PT and
aPTT as indicators of possible hepatic functional alteration
and vitamin K-dependent factor deciency. The brinogen
measurement performed by the traditional method (Clauss
method) allows for the identication of dysbrinogenemia,
i.e., a condition characterized by normal brinogen levelswith an altered biological activity. LAC tests, anti-beta2-glycoprotein-1 antibody assay, and anti-cardiolipin
antibody assay are the three diagnostic criteria for antiphospholipid antibody syndrome, and their positivity should be
conrmed after 12weeks. FV Leiden, unlike the wild-type
form, has an amino acid substitution makingit insensitive to
degradation by the activated protein complex C. FII
G20210A is associated with increased gene transcription
and increased circulating levels of prothrombin. Genetic
tests for C677T and A1298C mutations in the MTHFR gene
are no longer recommended in thrombophilia screening
because several evidences have shown that, although they
are associated with hyperhomocysteinemia, they do not
increase the risk for thromboembolism, neither in the venous
nor the arterial district. Similarly, genetic tests for 4G/5G
PAI-1, I/D ACE, a/b HPA-1, V34L FXIII, and -455G>A
FGB (beta-brinogen) mutations, previously considered as
part of thrombophilia screening, should no longer be performed due to lack of evidence supporting their involvement
in thrombosisrisk. The activated protein C resistance test
(APC resistance) can be performed as part of thrombophilia
screening if the conrmatory genetic test (FV Leiden) is
more expensive than the functional test or is not feasible.
However, the diffusion of lower-cost genetic tests in many
laboratories equipped for molecular diagnostics has made it
possible to bypass the functional assay and resort directly to
genetic testing.
The diagnosis of hereditary thrombophilia requires at least
one of the following conditions: ATIII deciency, protein C
deciency, protein S deciency, FVLeiden, and FII G20210A
mutations. However, a family history of venous thromboembolism without a corresponding biochemical or genetic nding should lead to the suspicion of hereditary thrombophilia
in selected cases. The search for FV Leiden and FII G20210A
mutations should be performed on rst- degree relatives of
subjects with these alterations and relatives of subjects with
ATIII, protein C, and protein S deciency. In any case, genetic
tests should be preceded by genetic counseling.
Factors Interfering withThrombophilia
Screening
Functional tests included in thrombophilia screening should
not be performed either during the acute phase of the thrombotic event or during anticoagulant therapy but at least 4 weeks
after discontinuation of therapy with vitamin K antagonists
since these tests may be falsied in these cases. Moreover, in
the case of liver disease, many of the tests included in the
thrombophilia screening may be altered (PT, ATIII, protein C,
protein S, factor VIII). Even during estroprogestin treatment
or pregnancy, thrombophilia screening should not be performed; it is necessary to wait at least 1 month after treatmentdiscontinuation or 2 months after childbirth. However,
these considerations do not apply to genetic tests. Moreover,
tests for the diagnosis of antiphospholipid antibody syndrome
can be performed during anticoagulant therapy.
Recommended Readings
Baglin T, Gray E, Greaves M etal (2010) Clinical guidelines for testing
for heritable thrombophilia. Br J Haematol 149(2):209–220
Bates SM, Greer IA, Pabinger I et al (2008) Venous thromboembo-
lism, thrombophilia, antithrombotic therapy, and pregnancy. Chest
133:844S–886S
Coppola A, Tufano A, Cerbone AM, Di Minno G (2009) Inherited
thrombophilia: implications for preven tion and treatment of venous
thromboembolism. Semin Thromb Hemost 35(7):683–694
Gohil R, Peck G, Sharma P (2009) The genetics of venous thromboem-
bolism. A meta-analysis involving approximately 120,000 cases and
180,000 controls. Thromb Haemost 102(2):360–370
McCormack T, Harrisingh MC, Horner D, Bewley S, Guideline
Committee (2020) Venous thromboembolism in adults: summary of
updated NICE guidance on diagnosis, management, and thrombophilia testing. BMJ 369:m1565
Seligsohn U, Lubetsky A (2001) Genetic susceptibility to venous
thrombosis. N Engl J Med 344(16):1222–1231
Simone B, De Stefano V, Leoncini E etal (2013) Risk of venous throm-
boembolism associated with single and combined effects of Factor
V Leiden, Prothrombin 20210A and Methylenetethraydrofolate
reductase C677T: a meta-analysis involving over 11,000 cases and
21,000 controls. Eur J Epidemiol 28(8):621–647
Testa S, Antonucci G, Intra E etal (2004) Gli screening per trombolia.
Riv Med Lab 5(2):118–120
(2020) Venous thromboembolic diseases: diagnosis, management
and thrombophilia testing. National Institute for Health and Care
Excellence (UK), London
Endocrine System
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MarcelloCiaccio, LuisaAgnello, GiuliaBivona,
AnnaMariaCiaccio, andBrunaLoSasso
25
Introduction
The endocrine system consists of a set of glands that, through
the release of hormones and in synergy with the nervous and
immune systems, regulate the various organs and apparatuses, contributing to maintaining homeostasis. The communication among the nervous, endocrine, and immune systems
includes complex regulatory circuits operating at different
functional levels. Laboratory medicine has an essential role
in understanding pathophysiological mechanisms involving
the endocrine glands and diagnosing diseases affecting the
glands. Studying circulating hormone levels provides valuable information to the clinician.
Hypophysis
MarcelloCiaccio and LuisaAgnello
Anatomy
The pituitary gland is an endocrine gland located in the center of the skull base, within the sella turcica; it consists of
two lobes, one anterior (adenohypophysis) and one posterior
(neurohypophysis), which are anatomically and functionally
distinct (Fig.25.1).
The saddle is contiguous with several vascular and neurological structures and anchored to the lower region of the
hypothalamus by the infundibulum, known as the pituitary
peduncle. The hypothalamus synthesizes release and inhibitory factors that are secreted directly into the portal vascular
system of the pituitary peduncle and, in turn, the pituitary
gland, in response, releases its hormones (Fig.25.2).
Pituitary hormones are pulsatile secreted and induce specic responses in various peripheral target tissues. In turn,
hormones released from peripheral tissues regulate pituitary
function through feedback at both hypothalamic and pituitary levels.
Diagnosis of pituitary disorders is mainly based on laboratory investigations to assess the function of the
hypothalamic- pituitary-target gland axis.
M. Ciaccio (*) · B. LoSasso
Department of Biomedicine, Neurosciences and Advanced
Diagnostics, Institute of Clinical Biochemistry, Clinical Molecular
Medicine and Clinical Laboratory Medicine, University Hospital
“P. Giaccone”, Palermo, Italy
Department of Laboratory Medicine, University Hospital “P.
Giaccone”, Palermo, Italy
e-mail: marcello.ciaccio@unipa.it
L. Agnello · G. Bivona
Department of Biomedicine, Neurosciences and Advanced
Diagnostics, Institute of Clinical Biochemistry, Clinical Molecular
Medicine and Clinical Laboratory Medicine, University Hospital
“P. Giaccone”, Palermo, Italy
A. M. Ciaccio
Department of Health Promotion, Mother and Child Care, Internal
Medicine and Medical Specialties (ProMISE) “G.D’Alessandro”,
University Hospital “P. Giaccone”, Palermo, Italy
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023
M. Ciaccio (ed.), Clinical and Laboratory Medicine Textbook, https://doi.org/10.1007/978-3-031-24958-7_25
Adenohypophysis
The anterior pituitary gland, also known as the adenohypophysis, accounts for about 80% of the entire gland and
produces six main hormones: Growth Hormone (GH),
Prolactin (PRL), Adrenocorticotropic Hormone or
Corticotropin (ACTH), Luteinizing Hormone (LH), FollicleStimulating Hormone (FSH), and Thyroid-Stimulating
Hormone (TSH). These hormones are also called pituitary
tropins because they maintain the tropism of the target
organs.
Growth Hormone
Growth hormone, or somatotropin, so dened for its ability
to increasestature growth in the hypophysectomized animal,
317
318
Hypothalamus
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M. Ciaccio et al.
Corpus callosum Thalamus
Pineal Gland
Encephalic trunk
Pituitary
Adenohypophysis Neurohypophysis
Fig. 25.1 Hypophysis. (Copyright EDISES 2021. Reproduced with
permission)
is the most abundant hormone of the adenohypophysis. Its
secretion occurs pulsatile every 3–4hours, with more frequent and intense peaks in the early hours of sleep (REM
phase [Rapid Eye Movement]); about 70% of daily GH
secretion occurs during sleep.
GH secretion is inversely correlated with age, being elevated in children and during the pubertal period and gradually decreasing over the years. In about 50% of samples
collected during the day in healthy and almost all elderly
subjects, GH levels cannot be assayed by standard methods. GH levels are higher in women than in men and
increase in both sexes following exercise, stress, trauma, or
sepsis.
Physiologically, GH secretion is controlled by two hypothalamic hormones, Growth Hormone–Releasing Hormone
(GHRH), with stimulatory action, and somatostatin (SRIH),
with inhibitory action. Physiological, pharmacological, and
pathological factors, regulating the secretion of GHRH and
SRIH at the hypothalamic level, regulate the secretion of GH
at the pituitary level. Dopamine, serotonin, acetylcholine,
sex steroids, and endogenous opioids have stimulant actions.
On the other hand, norepinephrine has a dual effect because
it increases GH secretion through the α-adrenergic pathway
and inhibits it through β
-adrenergic receptors. The insulinlike growth factor (IGF-1), which is the target of GH, through
a negative feedback mechanism, inhibits the production of
the hormone.
GH has a half-life ranging from 20 to 25minutes and is
metabolized mainly in the liver and, to a lesser extent, in the
kidney.
The main biological function of GH is to promote somatic
and tissue growth byregulating many metabolic processes
(Table 25.1). Many of the acute effects of GH are
insulin-like.
Fig. 25.2 Regulation of adenohypophysis hormone secretion. ACTH
adrenocorticotropic hormone, CRH corticotropin-releasing hormone,
FSH follicle-stimulating hormone, GH growth hormone, GHRH GH
releasing hormone, GnRH gonadotropin-releasing hormone, PHI-27
GnRH CRH
FSH
LH
GHRH
GH
Somatostatin Dopamine
TRH
TSH PRL
VIP
PHI-27
+ ++ +++
ACTH
––––
histidine-isoleucine-27 peptide, PRL prolactin, TRH thyrotropinreleasing hormone, TSH thyrotropic hormone, VIP Vasoactive intestinal peptide. (Copyright EDISES 2021. Reproduced with permission)
Hypothalamic
releasing
hormones
Adenohypophyseal
hormones
Hypothalamic
inhibitors
hormones
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319
Table 25.1 Metabolic action of growth hormone
Protein
metabolism
Lipid
metabolism
Carbohydrate
metabolism
Electrolytic and
mineral balance
Immune system Stimulates the trophism and function of the
HDL high density lipoprotein, LDL low density lipoprotein
Stimulates protein synthesis
Reduces protein catabolism
Reduces lipogenesis
Stimulates lipolysis
Stimulates the oxidation of fatty acids
Stimulates hepatic expression of LDL receptors
Promotes the production of HDL
Acute effects: stimulates insulin release and
increases glucose oxidation, resulting in lower
blood glycemia (insulin-like effect)
Late effects: the prolonged stimulus causes a
long- lasting anti-insulin effect characterized by
reduced peripheral glucose uptake and reduced
glycolysis, with consequent increase in blood
glucose
Promotes intestinal absorption of calcium and
phosphorus
Reduces the renal excretion of sodium and
potassium causing water retention
Stimulates the urinary excretion of calcium
Stimulates the hydroxylation of 25(OH)D a
1.25(OH)
calcium
thymus
D, promoting intestinal absorption of
2
GH exerts its biological action directly through interaction with a receptor located on the surface of target tissues
and indirectly through the IGF-1 factor, which stimulates its
synthesis mainly in the liver. The GH receptor is highly
expressed in the liver and cartilage. Once released into the
circulation, IGF-1 acts as a hormone, interacting with receptors target cells' surface. IGF-1 receptors have an almost
ubiquitous localization. In addition, IGF-1 secretion is also
stimulated at target tissues, especially cartilage, where it
stimulates growth by an autocrine/paracrine mechanism.
Physiological factors inuence serum concentrations of IGF-
1. In particular, levels increase during puberty with a peak
around 16years of age and progressively decrease until they
drop by 80% in elderly subjects. Women generally have
higher levels than men. Since GH is the primary regulator of
IGF-1 secretion, any alteration in its synthesis or action
(hypopituitarism, GHRH or GH receptor deciency) causes
a reduction in IGF-1 levels. Furthermore, the activity of the
GH/IGF-1 axis is strongly inuenced by nutritional status
and body composition. In particular, in obese subjects, GH
secretion, both spontaneous and stimulated, is markedly
reduced, with values overlapping those of patients with
severe GH deciency. At the same time, IGF-1 production
remains preserved, thus suggesting an alteration of the negative feedback control threshold. In cases of prolonged fasting, anorexia nervosa, and, in general, in chronic malnutrition,
there is an increase in GH and a reduction in IGF-1 levels.
Defects in the hypothalamic-pituitary axis can lead to low
GH levels (GH deciency) with signicant consequences in
children and adults or, vice versa, to hypersecretion of the
hormone (acromegaly).
Growth Hormone Deciency
Growth Hormone Deciency (GHD) is a clinical condition
caused by pathological GH deciency and, therefore, characterized by reduced stature growth in children and increased
body fat and reduced muscle mass in adults; adults with GH
deciency often complain of lack of energy and difculty
concentrating. GH deciency can present in very variable
forms with a clinical picture conditioned by the severity of
the hormonal decit (isolated or associated with other pituitary tropins) and by the age of onset. It is essential to identify GHD early, especially in children, as treatment with
recombinant human GH is highly effective in inducing an
increase in nal height.
GH Deciency inChildren
The deciency can be diagnosed at any age, but since infants
with GHD have an average birth weight and length, the slowdown in growth rate is usually noticed relatively late.
Characteristic signs of the decit, in addition to short stature,
are infantile facial features, delayed teething, small penis
(micropenis), and increased fat in the subcutaneous tissue
deposited on the hips and abdomen.
GHD can be congenital or acquired. Congenital causes
include structural malformations of the brain, for example,
abnormal development of the hypothalamus or pituitary
gland, and genetic mutations resulting in alterations in the
synthesis or function of GH or the receptor for GHRH or
peripheral tissue insensitivity due to structural defects in the
GH receptor or intracellular signal; in this case (peripheral
insensitivity to GH), we speak of a syndrome known as
Laron syndrome characterized by normal or elevated GH
levels associated with reduced IGF1 values and, in some
cases, reduced levels of GH-binding proteins (Growth
Hormone–Binding Proteins, GHBP).
Acquired GH deciency can be due to various causes.
The most frequent are benign tumors of the pituitary gland
(pituitary adenomas), which, as they grow, can damage the
remaining gland; less frequent causes include cranial irradiation, brain trauma, and central nervous system infections and
inammatory conditions (e.g., sarcoidosis). GH deciency
can occur in isolation or combination. In the latter case, GH
deciency is associated with the deciency of one or more
pituitary tropins and is generally due to mutations of transcription factors such as Pit-1 and Prop-1, which regulate the
differentiation of somatotropic cells of the
adenohypophysis.
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GH Deciency inAdults
Growth hormone deciency in adults is generally caused by
hypothalamic or pituitary damage, usually secondary to pituitary surgery, tumors, radiation treatment, or a developmental age deciency. Acquired pituitary insufciency has a
dened framework of functional decit in which loss of
adequate GH reserve precedes other tropin decits (GH, LH/
FSH, TSH, and ACTH).
GHD in adults is not dened by a characteristic clinical
picture. However, it presents nonspecic signs and symptoms, including an increase in body fat, especially visceral,
with an increase in the waist-to-hip ratio, a reduction in muscle mass, a reduction in bone density (osteopenia and osteoporosis) with an increased risk of fractures, reduced
performance during physical activity, and nally, alterations
in cardiovascular function. Thus, GHD in adults can manifest itself subtly and may not be easily recognizable on
clinical observation alone. GHD in adults must be suspected
in the presence of specic conditions.
Acromegaly
The term acromegaly identies a chronic syndrome caused
by GHhypersecretion during adulthood. An excess of GH
during childhood and puberty is accompanied by excessive
growth in height (gigantism). In adulthood, on the contrary,
being impossible, any further increase in length of the diaphysis, the disease causes a volumetric increase of the distal
parts of the body (bones and soft tissues); the term acromegaly derives from the Greek akros, extremities, and megas,
large. Acromegaly is characterized by swollen feet, hands
(the patient over the years is forced to change the size of the
rings and shoes), increased volume of the tongue, prognathism with consequent dental malocclusion, enlargement of
the facial bones, and organomegaly, i.e., the increase in the
volume of internal organs (heart, liver, thyroid, intestine, kidney, etc.), with consequent alteration of their function.
Patients with this pathology have a mortality rate three times
higher than the general population due to the increased risk
of cardiovascular, cerebrovascular, and respiratory diseases.
The process generally begins before age 40, but recognition of the disease can be very late, even after 10years, due
to the poor initial symptoms.
A GH-secreting pituitary adenoma sustains hormonal
hypersecretion in 95% of cases. In contrast, in the remaining very rare cases, it is due to GHRH hypersecretion of
intracranial (slow-growing hypothalamic adenomas, coristomas, ganglioneuromas) or extracranial origin, most frequently bronchial carcinoids, rarely neuroendocrine
tumors of the gastrointestinal tract and thymic carcinoids.
Cases of ectopic GH secretion by pancreatic, ovarian, pulmonary, or hematopoietic system tumors have also been
described.
Laboratory Investigations
Basal Measurement
GH
The basal serum GH assay is indicated in diagnosing GH
excess (acromegaly and gigantism) and controlling the
pathologies mentioned above after pharmacological therapy;
however, it has little diagnostic value in GH deciency. Since
GH is released in a pulsatile manner, performing the test at a
single time of day is usually not clinically indicative. The
most commonly used GH assay methods are based on monoclonal antibodies with enzymatic, uorescent, and chemiluminescent tracers.
The whole blood sample should be taken in the morning
on an empty stomach, in the patient in clinostat, and at rest
for 30minutes; exercise or stress conditions can signicantly
alter GH levels. Reference values in the healthy population
are reported in Table25.2, although it is not always possible
to measure GH levels in healthy subjects.
In contrast to the healthy subject, in patients with acromegaly, GH is always measurable, although it may be at normal limits in some cases.
IGF-1
IGF-1 reects GH deciency or excess, but unlike GH, its
levels are stable throughout the day. Therefore, measuring
IGF-1 levels is a helpful estimate of average GH levels.
Normal IGF-1 values vary with age and sex and depend on
the assay method used. The most commonly used assay
methods are radioimmunoassays and those based on chemiluminescent tracers.
Testing for the IGF-1 measurement may be required in
conjunction with the measurement of other pituitary hormones (PRL, FSH, or LH) to diagnose pituitary disorders.
Normal levels of IGF-1 indicate, with high probability, the
absence of GH abnormalities. However, the patient’s clinical
contextmust be always considered; some people may have
normal IGF-1 levels in the presence of GHD.Conversely,
decreased IGF-1 levels are strongly indicative of
GHD.Noteworthy, a decrease in IGF-1 can result from nutritional decits (anorexia nervosa), chronic kidney or liver disease, production of inactive forms of GH, and intake of high
doses of estrogen. Usually, elevated IGF-1 levels indicate
increased GH production.
During puberty and pregnancy, it is normal to detect
increased concentrations of GH and IGF-1; otherwise, they
are very often due to pituitary tumors.
Table 25.2 Normal values of GH
Men <5ng/mL or <226pmol/L
Women <10ng/mL or <452pmol/L
Children 0–20ng/mL or 0–904pmol/L
Newborns 5–40ng/mL or 226–1808pmol/L
GH growth hormone
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Finally, IGF-1 measurement helps monitor the treatment
of GH-secreting tumors. If the tumor is surgically removed,
measurement of IGF-1 and GH is an estimate of the actual
complete tumorremoval. If IGF-1 is still elevated after surgical removal of a pituitary tumor, then it may be that the surgery was not fully effective. Decreasing concentrations of
IGF-1 during subsequent drug therapy and/or radiation therapy indicate that the treatment is lowering GH production.
Increased IGF-1 levels may indicate pituitary tumor recurrence when a patient undergoes long-term monitoring.
Dynamic Measurement
The secretion of GH is pulsatile and episodic. Therefore, the
nding of a basal value close to zero is not diagnostic, as it is
also evident in normal subjects. In order to assess GH deciency, it is preferable to use a stimulus test by different
drugs administered alone or in combination.
The stimulation test is performed by collecting a blood
sample after fasting for 10–12hours. Then, under medical
supervision, a solution that stimulates the release of GH by
the pituitary gland is administered intravenously to the
patient. Subsequently, following stimulation, multiple blood
samples are collected at regular intervals to assess GH production by the pituitary gland.
The insulin-induced hypoglycemia test is the gold standard for diagnosing GH in adults because of its high sensitivity. When the hypoglycemic condition is reached, healthy
subjects have a GH peak within 60minutes, which persists
for the next 2hours; GHD in adults is diagnosed when GH
peak response to hypoglycemia below 5ng/mL. Although
the induced hypoglycemia test is safe when performed under
close medical supervision, it is contraindicated in elderly
subjects and patients at high cardiovascular risk. In addition,
obese normoglycemic or hyperglycemic patients with insulin resistance may not achieve an adequate hypoglycemic
state. Finally, although it has good sensitivity, it has poor
reproducibility. A viable alternative to the induced hypoglycemia test is the glucagon stimulus test. Other tests using
arginine or clonidine as the stimulating agent are available.
However,they present poor diagnostic accuracy. Glucagon is
more potent than other agents in inducing GH secretion.
Additionally, glucagon stimulates GH release more effectively when administered intramuscularly or subcutaneously
than intravenously.
Finally, enhanced stimulus tests are based on administering GHRH with other agents, most commonly arginine.
GHRH stimulates the synthesis and pituitary release of GH,
whereas arginine potentiates the stimulatory effect of GHRH
by inhibiting hypothalamic somatostatin release. The peak
GH response depends not on age or sex but onbody mass
index (BMI) and central adiposity. Its main advantages are
its reproducibility and high discriminatory power.
GH threshold values vary depending on the stimulus test
used. Table25.3 shows the main characteristics of the most
common stimulus tests.
The GH suppression test is indicated for the diagnosis of GH
excess and monitoring patients undergoing treatment. The oral
Glucose Tolerance Test (OGTT) is performed by collecting a
blood sample after fasting for 10–12hours. The patient is then
given a solution containing 75g of glucose dissolved in 300mL
of water. Subsequent blood samples, collected at regular time
intervals (30, 60, 90, and 120 minutes), make it possible to
assess whether the release of GH by the pituitary gland is correctly inhibited (the inhibitory action is linked to the activation
of endogenous secretion of somatostatin by glucose). In healthy
subjects, after 1 hour, GH is less than 1ng/mL, in patients with
GH hypersecretion, levels never fall below this value. However,
it should be kept in mind that the limit of normality for GH
values after OGTT varies according to the sensitivity of the
assay method used (1 ng/mL for conventional methods and
0.3–0.4ng/mL for ultrasensitive methods). In addition, it should
be considered that the following conditions may give false-positive results for lack of GH inhibition: malnutrition, depression,
renal or hepatic insufciency, diabetes mellitus, and obesity.
Diagnosis andTherapy
GH Deciency inChildren
The diagnosis of GH deciency in children is based on auxological criteria (stature decit associated with the reduced
growth rate), clinical, laboratory (altered response of GH to
pharmacological tests), and possibly neuroradiological ndings (abnormalities of the hypothalamic-pituitary region).
Based on these data, it will be possible to identify nonpathological conditions, dened as “normal variants” of growth,
such as short stature and constitutional growth retardation,
and diagnose the pathological forms.
Children with GHD may present a normal growth pattern
in the rst year of life, followed by a progressive slowing of
growth speed in the subsequent period. Suspicion of GH
deciency should be raised in the case of a child with short
stature and normal body proportions without
dysmorphisms.
A child is dened as short in stature when his/her height
is below the 3rd percentile or below 2 standard deviations
(SD). Short stature is found quite frequently in clinical prac-
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