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Ritmo circadiano, sistema immunitario e insufficienza surrenalica
Andrea M. Isidori
COMPOUND E and COMPOUND ABetween 1936 and 1938 Kendall’s group isolated and purified 20 chemicaladrenal compounds including Compound E (cortisone). By the same timeReichstein’s group in Basel isolated and purified 28 compounds includingCompound A (desoxycorticosterone).
By 1940 their work had allowed isolation of 28 adrenal steroids includingalso cortisol (Compound F) and corticosterone
And then…. World War II
… and the legend of a miraculous compoundused by pilots of Luftwaffe
The Nobel Prize in Physiology or Medicine 1950Edward C. Kendall, Tadeus Reichstein, Philip S. Hench
The Nobel Prize in
Physiology or Medicine 1950
The Nobel Prize in Physiology or Medicine 1950 was awarded jointly to Edward Calvin Kendall, Tadeus Reichstein and Philip Showalter Hench "for their discoveries relating to the hormones of the adrenal cortex, their structure and biological effects".
Edward C. KendallPrize share: 1/3
Tadeus ReichsteinPrize share: 1/3
Philip Showalter HenchPrize share: 1/3
INSUFFICIENZA CORTICOSURRENALICA
PRIMARIA
Arlt W. Allolio B. Lancet 2003Charmandari et al, Lancet 2014
TERAPIA SOSTITUTIVA CON GLUCOCORTICOIDI
SECONDARIA
TERZIARIA
SCHEMI DI TERAPIA
MANTENIMENTO STRESS MINORI STRESS MAGGIORI
EDUCAZIONE DEL PAZIENTE E DEI FAMILIARI
SCHEMA DI TRATTAMENTO
1. Terapia per la deficienza di glucocorticoidi
Cortisone acetato 25–37·5 mg die (BID-TID) Idrocortisone 15–25 mg die (BID-TID)
Steroide Dose equivalente (mg)
Potenza relativa anti-
infiammatoria
Potenza relativa mineralcorticoidea
Emivita plasmatica (h)
Emivita biologica (h)
Cortisone acetato 25 0.8 2 0.5 8-12
Idrocortisone 20 1 2 1.5-2 8-12
Metilprednisolone 4 5 0 1.5-3 18-36
Prednisone 5 4 1 1 18-36
Prednisolone 5 4 1 2-3.5 18-36
Triamcinolone 4 5 0 3.5-4 18-36
Betametasone 0.6-0.75 20-30 0 5.5 36-54
Desametasone 0.75 20-30 0 2-3.5 36-54
SCHEMA DI TRATTAMENTO
2. Terapia per deficienza di mineralcorticoidi (solo nel M. di Addison)
Fludrocortisone (Florinef) 50-250 mcg/die in dose unica (assunto al mattino)Iniziare con 100 mcg/die
Favorisce il ripristino ed il mantenimento del volume plasmatico e dell’equilibrio idro-salino extra ed intracellulare qualora la terapia cortisonica non sia sufficiente
3. Deidroepiandrosterone (opzionale)Pz con compromissione del tono dell’umoreDonne con segni e sintomi da insufficienza androgenicaDHEA 25–50 mg die in dose unica (assunto al mattino)
Charmandari et al, Lancet 2014
TERAPIA CONVENZIONALE CON GLUCOCORTICOIDI
IDROCORTISONE: farmaco di prima scelta
11• Ormone biologicamente attivo:
idrossilazione in posizione 11
• Concentrazione plasmatica:
picco dopo 1 ora dalla somministrazione;
dosabile nel sangue per circa 2 ore;
i suoi metaboliti sono misurabili fino a 4-7 ore
• Legato a proteine per circa il 90% (CBG e albumina) Forma attiva 5-10%
• Assorbimento intestinale ad opera della glicoproteina P
Farmaci che aumentano i livelli di CBG e che possono falsamente elevare i livelli di cortisolo
Estrogeni
Mitotane
IDROCORTISONE
• La fase I del metabolismo dell’idrocortisone è epatica (citocromo CYP3A4, isoenzima del citocromo P450):
Riduzione e Ossidazione
• La fase II: glucuronidazione e rilascio nel circolo enteroepatico ed eliminato tramite il circolo ematico per via renale (70-80%) e parte nelle feci (20-30%)
Farmaci che accelerano il metabolismo mediante induzione del CYP3A4
Fenobarbitale
Fenitoina
Carbamazepina
Primidone
Rifampicina
Etosuccimide
Pioglitazone
Farmaci che riducono il metabolismo mediante inibizione del CYP3A4
Itraconazolo
Ritonavir
Fluoxetina
Diltiazem
Cimetidina
0 20mg/m2/die
8-10
under-exposure adequate glucocorticoid replacement
androgenssuppression
negative effects on growth
15 17
over-exposure
Dosage titration
Webb EA et al, Current and novel approaches to children and young people with CAH and AI. Best practice and Research Clinical Endocrinologyand Metabolism 2015
safe
CORTISONE ACETATO
PRO FARMACO
Biologicamente attivo solo dopo idrossilazione nel fegato: l’80% è trasformato in cortisolo ad opera della 11β-HSD1 con perdita di circa 1/5 della dose efficace
Segue la stessa via di metabolizzazione dell’idrocortisone
CORTISONE ACETATO versus IDROCORTISONE
• Minore attività glucocorticoide e relativa mineralcorticoide
• Picco di massima concentrazione plasmatica ridotto
• Insufficienza epatica: impossibile idrossilazione nel fegato
• Deficit di 11β-HSD1: impossibile attivare il cortisone (molto rara)
• Sostanze endogene ed esogene (acidi biliari, carbenoxolone, liquirizia) possono inibirne l’attività
ALTRI GLUCOCORTICOIDI
• RITMO CIRCADIANO NON RISPETTATO
• AUMENTO DEGLI EFFETTI COLLATERALI
Steroide Dose equivalente
(mg)
Potenza relativa anti-
infiammatoria
Potenza relativa mineralcorticoidea
Emivita plasmatica (h)
Emivita biologica (h)
Metilprednisolone 4 5 0 1.5-3 18-36
Prednisone 5 4 1 1 18-36
Prednisolone 5 4 1 2-3.5 18-36
Betametasone 0.6-0.75 20-30 0 5.5 36-54
Desametasone 0.75 20-30 0 2-3.5 36-54
Terapia sostitutiva convenzionale con glucocorticoidi
Ridottobenessere
e qualità percepitadella vita
Mortalità
prematura
Ridottadensità minerale
ossea
Alteratoprofilo
metabolico
Steatosi epatica
Bergthorsdottir et al. JCEM 2006, Smans LCCJ et al. ECE 2011, Hahner et al. JCEM 2007 Filipsson et al. JCEM 2007, Zelissen et al. Ann Intern Med 1994; Lövås et al EJE 2009
Alta frequenza di ospedalizzazioni/
infezioni
“Infection was the death cause in 10% (5.1– 14.9) opposed to 6.0% in the general population.”
Erichsen MM et al. - Mortality in Addison’s disease - European Journal of Endocrinology (2009) Burman et al - Deaths Among Adult Patients with Hypopituitarism - J Clin Endocrinol Metab 2013
• Piu’di 40 anni per dimostrare gli effetti collaterali della terapia sostitutiva
• Riduzione dell’aspettatitiva di vita e di QoL, aumento della morbidità
• Rischio di crisi surrenaliche associate ad infezioni ed altri stress
• Rischio di sovradosaggio e fallimento nella gestione complessiva del paziente
NUOVE STRATEGIE TERAPEUTICHE
RIDURRE LA DOSE
MODIFICARE LA MODALITA’DI SOMMINISTRAZIONE
90 PZ: 57 PAI (42 F)33 CAH (21 F)
Divisi in 3 gruppi: 1) Non modifiche della dose di HC (N=50) 2) Aumento della dose di HC (N=13)3) Diminuzione della dose di HC (N=27)
Modification of GC replacement should be undertaken with care
Peak M Mah Clinical Endocrinology 2004;61:367–375.
Attempt to reduce AUC of GC exposure by reducing the peak dose might expose the risk toward immune system overreaction and/or chronic inflammatory state
Porter J et al, Immediate release granule formulation of HC, Alkindi, for treatment of pediatric AI. Expert review of endocrinology and metabolism 2018
Novel strategies for dosage titrationthe “old”….
the “new”
Circadian rhythm of cortisol in 33 individuals with 20-minute cortisol profiling
Circadian rhythm of cortisol
Chan S & De Bono M. Replication of cortisol circadian rhythm: new advances in hydrocortisone replacement therapyTher Adv Endocrinol Metab(2010) 1(3)
Il ritmo distingue gli esseri animati
«Circa diem»
• Physiology: circadian control of the immune system and its feedback mechanisms
• Pathophysiology: relevance of glucocorticoid circadian rhythm
• Adrenal Insufficiency: lack of studies on the immune system in patients on life-long treatment with glucocorticoids
• Recent studies: NK in Addison disease and ad interim results from the DREAM trial
• Perspectives: toward Chronopharmacology
Molecular circadian clockwork
Principal or core feedback loop CLOCK and BMAL1, form heterodimers to activate thetranscription of their target genes containing E-box element
These target genes include their negative regulators the Periods (PERs: PER1, PER2 and PER3) and the Cryptochromes (CRYs: CRY1 and CRY2). The concentration of BMAL1 is adjusted by an auxiliary or stabilizing feedback loop formed by the clock-controlled nuclear receptors REVERBα
Gi Hoon Son, Sooyoung Chung, Kyungjin Kim The adrenal peripheral clock: Glucocorticoid and the circadian timing system Frontiers in Neuroendocrinology 32 (2011) 451–465
• About 10% of the entire genome is under circadian control.
• More than 50% of all genes in the mouse genome oscillate with circadian rhythm somewhere in the body.
Zhang et al., PNAS 2015
Zhang et al., PNAS 2015
A circadian gene expression atlas: implications in medicine
Zhang et al., PNAS 2015
Circadian rhythm of cortisol in 33 individuals with 20-minute cortisol profiling
Circadian rhythm of cortisol
Chan S & De Bono M. Replication of cortisol circadian rhythm: new advances in hydrocortisone replacement therapyTher Adv Endocrinol Metab(2010) 1(3)
378 | JULY 2009 | VOLUME 5 www.nature.com/ nrendo
REVIEWS
The pathogenesis of chronic-stress-related disorders
can also be explained by sustained, excessive secretion
and effects of the major mediators of stress and sickness
syndromes, which influence the activities of multiple
homeostatic systems.2,3,9,30–36 These disorders thus rep-
resent chronic, maladaptive effects of two physio logical
processes whose mediators are meant to be secreted in a
quantity-limited and time-limited fashion but have gone
awry. The negative consequences of these effects are both
behavioral and somatic.
Behavioral and somatic consequences
The behavioral consequences of chronic stress result
from continuous or intermittent activation of the stress
and sickness syndromes, and prolonged secretion of
their mediators.2,7,8,12,41–47 Thus, CRH, norepinephrine,
cortisol and other hormones activate the fear system,
which produces anxiety, anorexia or hyperphagia; the
same mediators cause tachyphylaxis of the reward
system, which produces depression and cravings for
food, other substances or stress. These mediators also
suppress the sleep system, which causes insomnia, loss
of sleep and daytime somnolence. On the other hand,
IL-6 and other mediators, possibly in synergy with those
mentioned above, generate fatigue, nausea, headaches
and other pains. Executive and cognitive systems also
malfunction as a result of prolonged, chronic activa-
tion of stress and sickness syndromes and people may
perform and plan suboptimally and make and pursue
the wrong decisions. A vicious cycle is initiated and
sustained, in which be havioral maladjustment leads to
psychosocial problems in the family, peer group, school
and/or work, which sustain or cause further mediator
changes and exacerbate behavioral mal adjustment. The
young, developing brain is particularly vulner able, as it
lacks prior useful experiences to which it can resort.
The somatic consequences of continuous or inter-
mittent activation of the stress and sickness syndromes
can be equally devastating (or even worse) than their
behavioral consequences.2,3,7,8,27,31,41–47 In develop-
ing children, growth may be suppressed as a result of
a hypo functioning growth hor mone axis; in adults,
stress-induced hypo gonadism can manifest as loss of
libido and/or hypo ferti lity, and hyperactivity of the
sympathetic system can lead to essential hypertension.
Chronic hypersecretion of stress mediators, in indivi-
duals with a vulnerable background exposed to a permis-
sive environment, may lead to visceral fat accumu lation
as a result of chronic hypercortisolism, reactive insulin
hyper secretion, low growth-hormone secretion and
hypogonadism (Figure 2).2,3,27,47–52 These same hormonal
changes lead to sarcopenia, osteo penia and/or osteo-
porosis. Visceral obesity and sarco penia are associ ated
with manifestations of the metabolic- syndrome, such
as dyslipidemia (elevated levels of total cholesterol, tri-
glycerides and LDL-cholesterol and decreased level
of HDL-cholesterol), hypertension and carbo hydrate
in tolerance or type 2 diabetes mellitus. Genetically or
constitutionally vulnerable women of reproductive age
may develop polycystic ovary syndrome. Stress-related
IL-6 hypersecretion plus adipose-tissue-generated
inf lammatory hypercytokinemia, as well as hyper-
cortisolism, contribute to increased production of
acute-phase reactants and blood hypercoagulation.49–52
Insulin resistance, hypertension, dislipidemia, hyper-
cytokinemia and blood hypercoagulation lead to endo-
thelial dysfunction and consequently atherosclerosis ,
with its cardio vascular and neurovascular sequelae.
Chronic-stress-induced immune dysfunction, pri-
marily the TH1 to T
H2 switch, increases the vulner ability of
indivi duals to certain infections and autoimmune dis-
orders (Figure 1).6–8,29–31,34 For instance, the immune dys-
function observed in individuals who are chronically
stressed might contribute to the persistence of infection
with Helicobacter pylori, granted that this pathogen
Box 3 | Conditions with altered HPA axis activity2
Increased activity of the HPA axis
Cushing syndrome ■
Chronic stress ■
Melancholic depression ■
Anorexia nervosa ■
Obsessive–compulsive disorder ■
Panic disorder ■
Excessive exercise (obligate athleticism) ■
Chronic, active alcoholism ■
Alcohol and narcotic withdrawal ■
Diabetes mellitus ■
Central obesity (metabolic syndrome) ■
Post-traumatic stress disorder in children ■
Hyperthyroidism ■
Pregnancy ■
Decreased activity of HPA axis
Adrenal insufficiency ■
Atypical/ seasonal depression ■
Chronic fatigue syndrome ■
Fibromyalgia ■
Premenstrual tension syndrome ■
Climacteric depression ■
Nicotine withdrawal ■
Following cessation of glucocorticoid therapy ■
Following Cushing syndrome cure ■
Following chronic stress ■
Postpartum period ■
Adult post-traumatic stress disorder ■
Hypothyroidism ■
Rheumatoid arthritis ■
Asthma, eczema ■
Abbreviation: HPA, hypothalamic–pituitary–adrenal.
nrendo_106_JUL09.indd 378 4/6/09 19:04:04
378 | JULY 2009 | VOLUME 5 www.nature.com/ nrendo
REVIEWS
The pathogenesis of chronic-stress-related disorders
can also be explained by sustained, excessive secretion
and effects of the major mediators of stress and sickness
syndromes, which influence the activities of multiple
homeostatic systems.2,3,9,30–36 These disorders thus rep-
resent chronic, maladaptive effects of two physio logical
processes whose mediators are meant to be secreted in a
quantity-limited and time-limited fashion but have gone
awry. The negative consequences of these effects are both
behavioral and somatic.
Behavioral and somatic consequences
The behavioral consequences of chronic stress result
from continuous or intermittent activation of the stress
and sickness syndromes, and prolonged secretion of
their mediators.2,7,8,12,41–47 Thus, CRH, norepinephrine,
cortisol and other hormones activate the fear system,
which produces anxiety, anorexia or hyperphagia; the
same mediators cause tachyphylaxis of the reward
system, which produces depression and cravings for
food, other substances or stress. These mediators also
suppress the sleep system, which causes insomnia, loss
of sleep and daytime somnolence. On the other hand,
IL-6 and other mediators, possibly in synergy with those
mentioned above, generate fatigue, nausea, headaches
and other pains. Executive and cognitive systems also
malfunction as a result of prolonged, chronic activa-
tion of stress and sickness syndromes and people may
perform and plan suboptimally and make and pursue
the wrong decisions. A vicious cycle is initiated and
sustained, in which be havioral maladjustment leads to
psychosocial problems in the family, peer group, school
and/or work, which sustain or cause further mediator
changes and exacerbate behavioral mal adjustment. The
young, developing brain is particularly vulner able, as it
lacks prior useful experiences to which it can resort.
The somatic consequences of continuous or inter-
mittent activation of the stress and sickness syndromes
can be equally devastating (or even worse) than their
behavioral consequences.2,3,7,8,27,31,41–47 In develop-
ing children, growth may be suppressed as a result of
a hypo functioning growth hor mone axis; in adults,
stress-induced hypo gonadism can manifest as loss of
libido and/or hypo ferti lity, and hyperactivity of the
sympathetic system can lead to essential hypertension.
Chronic hypersecretion of stress mediators, in indivi-
duals with a vulnerable background exposed to a permis-
sive environment, may lead to visceral fat accumu lation
as a result of chronic hypercortisolism, reactive insulin
hyper secretion, low growth-hormone secretion and
hypogonadism (Figure 2).2,3,27,47–52 These same hormonal
changes lead to sarcopenia, osteo penia and/or osteo-
porosis. Visceral obesity and sarco penia are associ ated
with manifestations of the metabolic- syndrome, such
as dyslipidemia (elevated levels of total cholesterol, tri-
glycerides and LDL-cholesterol and decreased level
of HDL-cholesterol), hypertension and carbo hydrate
in tolerance or type 2 diabetes mellitus. Genetically or
constitutionally vulnerable women of reproductive age
may develop polycystic ovary syndrome. Stress-related
IL-6 hypersecretion plus adipose-tissue-generated
inf lammatory hypercytokinemia, as well as hyper-
cortisolism, contribute to increased production of
acute-phase reactants and blood hypercoagulation.49–52
Insulin resistance, hypertension, dislipidemia, hyper-
cytokinemia and blood hypercoagulation lead to endo-
thelial dysfunction and consequently atherosclerosis ,
with its cardio vascular and neurovascular sequelae.
Chronic-stress-induced immune dysfunction, pri-
marily the TH1 to T
H2 switch, increases the vulner ability of
indivi duals to certain infections and autoimmune dis-
orders (Figure 1).6–8,29–31,34 For instance, the immune dys-
function observed in individuals who are chronically
stressed might contribute to the persistence of infection
with Helicobacter pylori, granted that this pathogen
Box 3 | Conditions with altered HPA axis activity2
Increased activity of the HPA axis
Cushing syndrome ■
Chronic stress ■
Melancholic depression ■
Anorexia nervosa ■
Obsessive–compulsive disorder ■
Panic disorder ■
Excessive exercise (obligate athleticism) ■
Chronic, active alcoholism ■
Alcohol and narcotic withdrawal ■
Diabetes mellitus ■
Central obesity (metabolic syndrome) ■
Post-traumatic stress disorder in children ■
Hyperthyroidism ■
Pregnancy ■
Decreased activity of HPA axis
Adrenal insufficiency ■
Atypical/ seasonal depression ■
Chronic fatigue syndrome ■
Fibromyalgia ■
Premenstrual tension syndrome ■
Climacteric depression ■
Nicotine withdrawal ■
Following cessation of glucocorticoid therapy ■
Following Cushing syndrome cure ■
Following chronic stress ■
Postpartum period ■
Adult post-traumatic stress disorder ■
Hypothyroidism ■
Rheumatoid arthritis ■
Asthma, eczema ■
Abbreviation: HPA, hypothalamic–pituitary–adrenal.
nrendo_106_JUL09.indd 378 4/6/09 19:04:04
Conditions with altered HPA axis activity
Chrousos GP. Stress and disorders of the stress system. Nat Rev Endocrinol 2009;5:374–381
Alterations in its rhythmicity are frequently found in many human diseases
Although the precise significance of the daily GC rhythm is not yet well established, a growing body of evidence does point to its clinical importance.
Circadian control of the immune system:- cyclical release for the haematopoietic niche- cyclical recruitment of immune cells to tissues
Rest Activity Activity Rest
24/0 12 24/0
Recruitment of HSCs (haematopoietic stem cell) and
mature immune cells to tissues
Numbers of HSCs and mature immune cells in blood
Cortisol
1. Clock’s gene expression2. Oscillations in adhesion molecules and
chemokines by endothelial cells 3. Oscillations in pro-migratory factors
(homing to tissues at specific stages of circadian cycle)
CXCL12 levels in bone marrow
P-selectin, E-selectin,VCAM1 and ICAM1
levels on endothelial cells
Rest Activity Activity Rest
24/0 12 24/0
Adapted from: Scheiermann C et al. Nat Rev Immunol 2013;13:190.Lightman SL et al. Nat Rev Neurosci. 2010 Oct;11:710.
4. Hormonal regulation and sympathetic nerves stimulation
HPA control of immune circadian rhythm
Scheiermann C et al. Nat Rev Immunol 2013;13:190.
CRH
ACTH, adrenocorticotropic hormone; SNS, sympathetic nervous system; MIF, macrophage inhibitory factor; CRH, Corticotropin-releasing hormone; SCN, suprachiasmatic nuclei
Interleukins
The HPA-immunity counter-regulatory feedback (1)
Light activates the adrenal gland
A. Ishida, T. Mutoh, T. Ueyama, H. Bando, S. Masubuchi, D. Nakahara, G. Tsujimoto, H. Okamura, Light activates the adrenal gland: timing of gene expression and glucocorticoid release, Cell Metab. 2 (2005) 297–307.
Per1-luc luminescence in visceral organs
HOW?
Circadian Metabolism
in the Light of Evolution
Endocr Rev. 2015;36(3):289-304
Sunlight, temperature, physical activity, and food intake serve as basic entraining cues, or zeitgebers, to reset
the master clock (A)
in the hypothalamic SCN each day.
Dexamethasone induces circadian gene expression1
GRAlfpCre mice with a liver-specific disruption of the GR gene
The glucocorticoid receptor (GR) is required for dexamethasone-induced Per1 phase shifting1
Cortisol synchronizes peripheral clocks
1. Balsalobre A et al. Science 2000;289:2344-2347; 2. Gi Hoon Son et al. Frontiers in Neuroendocrinology 2011;32:451–465.
DBP, TBP
4h shift
Nader, N., Chrousos, G. P., Kino, T. Circadian rhythm transcription factor CLOCK regulates the transcriptional activity of the glucocorticoid receptor by acetylating its hinge region lysine cluster: potential physiological implications. FASEB J. 23, 1572–1583 (2009)
The clockwork influenceresponsiveness to
glucocorticoids
The Clock-HPA axis counter-regulatory feedback (2)
Clock/Bmal1 physically interact with the ligand-binding domain of the GR through a regionenclosed in the C-terminal part of the Clock protein, and suppressed GR-inducedtranscriptional activity
The clockwork influence responsiveness to GC
Nancy Nader et al Trends Endocrinol Metab. 2010 May ; 21(5): 277–286.
By disrupting the clock -> we can alter the efficacy (side effects) of GC
Figure 2.
The circadian CLOCK system and the HPA axis influence each other’s activity at multiple
levels. The central CLOCK under the regulation of the light input controls the HPA axis and
produces regular diurnal secretion of glucocorticoid hormones from the adrenal glands, while
the peripheral CLOCKs, which is located in the adrenal glands and other components of the
HPA axis and are regulated by the central CLOCK through the sympathetic nervous system,
also contribute to the rhythmic glucocorticoid secretion from these organs. Secreted
glucocorticoids in turn reset and phase-delay circadian rhythm of the peripheral CLOCKs by
stimulating the expression of several CLOCK-related genes; this is especially important for
temporal adjustment of body’s activity against stress. The peripheral CLOCKs also regulate
glucocorticoid effect in local tissues through interaction between Clock/Bmal1 and GR,
providing a local counter regulatory feedback loop to the effect of central CLOCK on the HPA
axis.
Nader et al. Page 12
Trends Endocrinol Metab. Author manuscript; available in PMC 2010 May 4.
NIH
-PA
Au
tho
r Ma
nu
scrip
tN
IH-P
A A
uth
or M
an
uscrip
tN
IH-P
A A
uth
or M
an
uscrip
t
Interactions of the Circadian CLOCK System and the HPA Axis
Nancy Nader et al Trends Endocrinol Metab. 2010 May ; 21(5): 277–286.
MMIF
Arjona A & Sarkar DK Neurochem Res 2008;33:708–718.
Circadian gene disruption on the immune system
Several GREs elements
Glucocorticoids
Clock-genes
CCG genes:• STAT3, • STAT5, • NF-κB
v
vv
vv
v
Some monocytes got rhythm22- Circadian timing in disease manifestations3,4
Disease or model Oscillating parameter AcrophaseRheumatoid arthritis Stiffness, pain, serum TNF, serum IL-6 CT5–CT8 Allergic rhinitis Sneezing, nasal congestion CT6 Bronchial asthma Bronchoconstriction CT6
Sputum eosinophils, serum IL-5 CT7 Myocardial infarction Pain CT9 Ischaemic stroke Hypertension CT6–CT12Sickle cell vaso-occlusion Crisis (hospitalization) CT18
1- Circadian response to acute inflammatory insults1,2
In animals it is proven that over-reaction to pathogens (and their by-products) lead to increased lethality in circadian related mechanism!
Is immune circadian rhythm relevant?
1. Shackelford et al. Science 1973;182:285–287. 2. House SD et al. Life Sci 1997;60:2023–2034, Khoa D Nguyen et al. Science 2013;341:1483. Druzd D & Scheiermann C Science 2013;341:1462.3. Gibbs J E et al. Proc Natl Acad Sci USA 2012;109:582–587.4. Scheiermann C et al. Nat Rev Immunol 2013;13:190.
Symptoms of circadian clock mutant animals and human glucocorticoid dysregulation
Gi Hoon Son, Sooyoung Chung, Kyungjin Kim. Frontiers in Neuroendocrinology 2011;32:451–465.
Primary adrenal insuficiency was
associated with a 2–3 fold increased
mortality rate compared with the
background population
Mortality risk in patients with addison’s disease
• The idea that GCs are only immunosuppressive is over simplistic:
1. Circadian rhythm in immune cells regulates cells formation and extravasation to target tissues
2. GCs synchronize endogenous clocks in immune and endothelial cells
3. Circadian rhythm in immune cells controls anticipatory response and pathogen-driven response preventing overreaction
• Disruption of circadian rhythm in immune cells could be linked to time-clustered diseases (myocardial infarction, atheroma plaque rupture, autoimmune exacerbations…)
GC clocks immunity
Scheiermann C et al. Nat Rev Immunol 2013;13:190.Lightman SL et al . Nat Rev Neurosci. 2010 Oct;11:710House SD et al. Life Sci 1997;60:2023–2034Khoa D Nguyen et al. Science 2013;341:1483.
Druzd D & Scheiermann C Science 2013;341:1462.Gibbs J E et al. Proc Natl Acad Sci USA 2012;109:582–587.Scheiermann C et al. Nat Rev Immunol 2013;13:190.Gi Hoon Son et al. Front. in Neuroendocrinol. 2011;32:451–465
Immune function in adrenal insufficiency: neglected area of research
185 related to immunological pathogenesis of autoimmune Addison
9 describing the immune phenotype in AI (miRNA, cytokines)
0 describing myeloid subpopulations
NUOVE STRATEGIE TERAPEUTICHE
Dual-release hydrocortisone preparations
Rivestimento esterno
Nucleo centraleØ 8 mm
LI=liberazione
Immediata
LL= Liberazione Lenta
G. Johannsson et al 2012A.Falorni et al 2013
Unica somministrazione giornaliera per os la mattina al risveglio
La compressa non è divisibile e non deve subire alterazioni chimico-fisiche
Dose di mantenimento 20-30 mg
Dosaggio inferiore in pz con una minima quota di cortisolo endogeno
40 mg dose massima studiata
Clock time 06.00 12.00 18.00 24.0000.00
0
200
400
600
800 Immediate release hydrocortisone tablet
Dual-release HC tablet
Improved Serum Cortisol Profilewith Dual-Release HC tablet
0-24 h
(8 AM-8
AM)
Total exposure 19%
lower on Dual-release
than TID
0-4 h
(8 AM-
12.00)
Morning exposure 6%
higher on Dual-
release than TID
4-12 h
(12.00-8
PM)
Afternoon and early
evening exposure
38% lower on Dual-
release than TID
12-24 h
(8 PM-
8AM)
Night exposure 41%
lower on Dual-release
than TID
Cortisol conc. (nM)
Johannsson G et al. J Clin Endocrinol Metab 2012;97:473–481
The DREAM trial - NCT02277587
Dual RElease Hydrocortisone Versus conventionAl Glucocorticoid replaceMent
Therapy in Hypocortisolism
MCEL: molecular and cellular endocrinology lab, 1Sapienza University of Rome, Rome, Italy
2Università Federico II, Naples, Italy
Spontaneous non-sponsored trial
Controls
Secondaryadrenal insuf.
Primaryadrenal insuf.
Randomisation
Standard Multiple times daily GC
Once-daily MR hydrocortisone
FACsSerumDEXA
Epicardial fatHepatic fat
FACsserum
FACsserum
FACsserum
FACsserumDEXA
Epicardial fatHepatic fat
T=0 1 month
2 months
3 months
6 months
Once-daily MR hydrocortisone
Standard Multiple times daily GC
Standard GC could be IRHC TID or BID or cortisone acetate
Isolation of peripheral blood mononuclear cells
CD14/CD16/ CD56/CD3 labelling
Flow cytometry
analysis
CD
16
CD14+ CD16-Classical monocytes(pro-inflammatory)
CD16+CD14-
Isidori AM et al. Abstract presented at ENDO 2015: PP17-4.
Monocytes
Lymphocytes
CD16+ CD14+(Anti-inflammatory) monocytes
CD14
Healthy Subject
Isidori Venneri et al. The Lancet. Diabetes & Endocrinology, 2017
Endocr Rev. 2015;36(3):289-304Isidori et al. Lancet Diabetes Endocrinol. 2018 Mar;6(3):173-185.
4 wks of DR hydrocortisone
ADDISON’S disease
Male patients #1
Leuko: 6.6 X 103
Neutro: 41.4%Mono: 7.3%Lympho: 44.5%Eosi: 4.8%Baso: 0.7%Luc: 1.2%ESR: 3Fibr: 2.13PCR: 600 ml/dl
Leuko: 5.46 X 103
Neutro: 49.8%Mono: 6.1%Lympho: 36.5%Eosi: 5.5%Baso: 0.7%Luc: 1.4%ESR: 2Fibr: 1.81PCR: 800 nm/dl
HC 15 + 5 mgDual-release
hydrocortisone 20 mg
19%
10.5% 2.9%
56%
0.4% 6.6%
48%
0.2% 3.6%
Before switching treatment
12%
19% 2%
8 wks of DR hydrocortisone
12 wks of DR hydrocortisone
Isidori AM et al. Abstract presented at ENDO 2015: PP17-4. DREAM trial ad interim analysis.
Female patients #8
Leuko: 6.8 X 103
Neutro: 48.1%Mono: 3.1%Lympho: 44.7%Eosi: 1.3%Baso: 0.3%Luc: 1.7%ESR: 9Fibr: 4.45 g/LPCR: 500 mg/dl
Leuko: 8.8 X 103
Neutro: 74.6%Mono: 4.4%Lympho: 18.6%Eosi: 0.9%Baso: 0.1%Luc: 1.4%ESR: 8Fibr: 3.28 g/LPCR: 700 mg/dl
HC 15 + 5 mg
63 %
0.1% 1 %
18.5 %
11% 4.3 %
50 %
0.1% 0.3 %
Before switching treatment
12.5 %
7% 4 %
12 wks of DR hydrocortisone
4 wks of DR hydrocortisone
8 wks of DR hydrocortisone
Dual-release hydrocortisone 20 mg
ADDISON’S disease
Isidori AM et al. Abstract presented at ENDO 2015: PP17-4. DREAM trial ad interim analysis.
Male patients #5
Before switching treatment
Secondary AI (hypopit)
51% 55%
4.1% 0% 1%14.0%
24%
11.1% 3.1%
Leuko: 6.28 X 103
Neutro: 52.6%Mono: 6.4%Lympho: 35.5%Eosi: 3.2%Baso: 0.3%Luc: 1.8%ESR: 12Fibr: 3.35 g/LPCR: 1300 mg/dl
Leuko: 6.9 X 103
Neutro: 56.7%Mono: 7.0%Lympho: 30.0%Eosi: 4.5%Baso: 0.1%Luc: 1.6%ESR: 22Fibr: 3.47 g/LPCR: 2800 mg/dl
Cortisone acetate
29%
10.6% 3.6%
Dual-release hydrocortisone 20 mg
4 wks of DR hydrocortisone
12 wks of DR hydrocortisone
8 wks of DR hydrocortisone
Isidori AM et al. Abstract presented at ENDO 2015: PP17-4. DREAM trial ad interim analysis.
Controls
sAI
CD14+ CD16- monocytes are increased in AI patients
CD14+ CD16- (% cells)
Classical monocytes
(pro-inflammatory)
sAI on CGC
pAI on CGC
CD16+ CD14- (% cells)
NK and NKT
Isidori et al. Lancet Diabetes Endocrinol. 2018 Mar;6(3):173-185.
CD16 expression on NK cells defined as CD56+CD3-
CD
56
CD16
Controls
AI patients
Total numberof CD56+ NK cells does not differ amongthe different groups
CD16+ NK cellsreduction
How NK cells Kill?
-Antibody dependent cytotoxicity-Recognition of altered surface molecules
Mediated by:-Perforin-Granzymes:-TNF-alfa
Beltran Front. Immunol., 2014
Shift timing of GC replacement affect circulating monocytes and NK cells in AI patients
Calssical (inflammatory)Monocytes
% of CD16+ NK cells….OKAY, ….but the mechanism?
Once-daily
Multiple-daily
Isidori et al. Lancet Diabetes Endocrinol. 2018 Mar;6(3):173-185.
CD16 regulation in NK cells
Romee et al. Blood 2013
ADAM17
Soluble CD16
…then is the CD16 Lost?
Isidori - Venneri et al. The Lancet. Diabetes & Endocrinology, 2017
Does it matters?
Correlation between immune changes and infection score
Isidori - Venneri et al. The Lancet. Diabetes & Endocrinology, 2017
Core clockwork in innate immunity
Scheiermann et al, Nature Reviews Immnunoly 2018
Importance of a functional clock in regulating the daily flux of inflammatory cellsbetween bone marrow, blood and immune organs under homeostatic conditions
Total PBMCs
Sorted by cell type:- Lympho- Mono
Pooled patientsby treatment group
Individually analysed Patients
PCR amplification in Real time PCR array predesigned 96-well panel for use with SYBR® Green Circadian rhythms (SAB Target List) H96
Heat map of the transcriptome at baseline
Clock gene group CREB signaling gene group
Transcription gene group Other Circadian Related
19 genes displayed a statistically different level of expression in PBMCs drawn from healthy vs AI subjects
Impact of switching glucocorticoids replacement therapy
12-weeks posttreatment switch:
multiple once daily glucocorticoid
administration
***
Differentially modulated genes in all groups at baseline and after treatment
PER3 plays an interesting role inadipogenesis homeostasis byregulating Klf15, a pivotal genein adipocyte differentiation.
Aggarwal et al Cell Rep. 2017
Differentially modulated genes in all groups at baseline and after treatment
***
Perforin forms membrane pores that
allow the release of granzymes and
subsequent cytolysis of target cells.
PRF1 deficiency -> IMMUNE DEFECT
Differentially modulated genes in all groups at baseline and after treatment
***
PRF1 Adipose Tissue Inflammation
PER3 Impaired Adipogenesis
Differentially modulated genes in all groups at baseline and after treatment
CREB is induced by a variety of growth factors and inflammatory signals; it can promote anti-inflammatory immune responses, through inhibition of NF-kB, induction of IL-10, but it is also considered a nutrient-sensing transcriptional regulatory proteins (with FOXO-p300, PGC-1, and SP1 family members).
Wen A e al. J Immunol 2010
**
J Clin Endocrinol Metab, August 2018, 103(8):2998–
3009
Resetting the expression () of 9.00 AM clock-related genes correlates with the improvement in clinical outcomes (metabolism, inflammation, infections).
Perspectives: toward better Chronopharmacology
Non-physiological cortisol replacement in adrenal insufficiency
Peak M Mah Clinical Endocrinology 2004;61:367–375.
The non-physiological circadian profile rather than the dose could be the major explanation for the AI outcome
FrequentAbnormal
RE-SYNC ? ! ?
Immediate release HC (TID) in patients with AI does not mimick cortisol rhythm by giving multiple peaks and nadirs
Single Pulse GC
Immune cell oscillation
Multiple Pulses GC
Immune cell oscillation
In-phase amplified oscillation
Out-phase disrupted oscillation
Fixing the broken clock?
J Clin Endocrinol Metab, September 2018, 103(9):3511–
3513
GC fluctuations postively and negatively affect memory
COSA BISOGNA SAPERE SUL PLENADREN
Per il passaggio da terapia convenzionale a plenadren è di aiutol’applicazione CORTICONVERTER
Nella pratica clinica il passaggio da Idrocortisone BID o TIDa plenadren prevede lo stesso dosaggio
A causa della minore biodisponibilità del plenadren bisogna monitorare sempre la risposta clinica ed eventualmente
personalizzare la dose
Nei pazienti affetti da Insufficienza corticosurrenalica secondaria, in trattamento conaltri ormoni, ad esempio GH, la posologia del plenadren non va modificata
In presenza di IPOTIROIDISMO, iniziare prima la terapia con Plenadren e successivamente con Levotiroxina sodica
COSA BISOGNA SAPERE SUL PLENADREN
MALATTIE INTERCORRENTI
NON sottovalutare il rischio di crisi surrenalica
Raddoppiare il dosaggio di glucocorticoidi in caso di FEBBRE o di altre patologie, triplicare per temperatura corporea > 39°assumendo un’altra compressa di Plenadren dopo almeno 8 ore dalla precedente senza modificare la dose del mattino
•In alternativa somministrare compresse di Idrocortisone a rilascio immediato
In caso di vomito persistente e/o diarrea bisogna somministrareGlucocorticoidi per via i.m. o endovena
NON SOTTOVALUTARE MAI LA PRESENZA DI INFEZIONI
A.Falorni et al 2013G. Johannsson 2015
COSA BISOGNA SAPERE SUL PLENADREN
INTERVENTI CHIRURGICI MINORI
La dose sostitutiva giornaliera deve essere aumentata termporaneamente
INTERVENTI CHIRURGICI MAGGIORI
Richiedono la somministrazione diGlucocorticoidi per via endovenosao intramuscolare
Terapia per os una volta che il pazientesi alimenta
Assumere un’altra compressa di Plenadren dopo almeno 8 ore dalla precedente senza modificare la dose del mattino
COSA BISOGNA SAPERE SUL PLENADREN
POPOLAZIONI SPECIALI
ANZIANI: dose inferiore soprattutto in relazione a peso ed età
INSUFFICIENZA RENALE: LIEVE/MODERATA, nessun aggiustamento della dose GRAVE, monitoraggio clinico stretto ed eventuale aggiustamento della dose
INSUFFICIENZA EPATICA: LIEVE/MODERATA, nessun aggiustamento della dose
GRAVE, monitoraggio clinico stretto
ed eventuale aggiustamento della dose
HIV: Aggiustamento posologia in relazione al dosaggio di farmaci antiretrovirali
FERTILITA’, GRAVIDANZA E ALLATTAMENTOIl plenadren non ha nessun effetto negativo sulla fertilità e puòessere usato in gravidanza e durante l’allattamento
formulation, DIURF-006, when given asa twice-daily ‘toothbrush’
regimen, 20 mg at night (23:00 h) and 10 mg in the morning
(07:00 h) provided cortisol exposure similar to that seen in
physiological cortisol levels in a healthy reference population
and also to that seen in dexamethasone-suppressed healthy volun-
teers after a single dose of 30-mg hydrocortisone. The relative
(a)
(b)
(c)
Fig. 4 (a) Dose–response of DIURF-006; 5,
10 and 20 mg (Geomean SEM). (b) Dose
proportionality for DIURF-006; 5, 10 and 20 mg
AUC (Geomean SD). Dotted line represents the
regression line: Slope: 0 69, 95% CI 0 65–0 73. (c)
Twice-daily dosing at 23:00 and 07:00 h with
DIURF-006; 20 and 10 mg in dexamethasone-
suppressed healthy male volunteers.
© 2013 John Wiley & Sons Ltd
Clinical Endocrinology (2014), 80, 554–561
Modified-release hydrocortisone mimics cortisol rhythm 559
Twice-daily dosing at 23:00 and 07:00 h with DIURF-006; 20 and 10 mg in dexamethasone- suppressed healthy male volunteers.
DIURF-006
Dose–response of DIURF-006; 5, 10 and 20 mg
Chronocort formulation,DIURF-006,when given as a twice-daily‘toothbrush’ regimen, 20 mg at night (23:00 h) and 10 mg in the morning(07:00 h) provided cortisol exposure similar to that seen in physiological cortisol levels in a healthy reference population and also to thatseen in dexamethasone-suppressed healthy volunteers after a single dose of 30-mg hydrocortisone.
Modified-release hydrocortisone tablet to provide circadian profile
Migliore esposizionesistemica al cortisolonelle prime ore notturne
• Microinfusore sottocutaneo: idrocortisone 50mg/ml (durata 3 giorni)
• 10 mg/m2 per superficie corporea die
• Simulazione della normale secrezione circadiana di cortisolo
• Replicando il normale ritmo del cortisolo:
riduzione di ACTH e miglioramento QoL
• Costo: pz selezionati in cui non si riesce ad ottenere un compenso con la tradizionale terapia
LA CRISI SURRENALICA
• Fattori precipitanti: patologie GI (32.6%) e altre cause infettive soprattutto simil-influenzali (24.3%)
• 1 su 12 ha una crisi surrenalica che mette a rischio la sua vita nel corso di un anno
Hahner S. et al. EJE. 2010;162:597– 602White K. Et al. EJE. 2010; 162:115–120 Hahner S. et al .JCEM. 2015;100:407– 416
Articolo - Autore N N° crisi surrenaliche
Hahner S. et al. EJE. 2010
444 6.6/100 anno
White K. Et al 2010 841 8/100 anno
Hahner S. et al. JCEM, 2015
768 8.3/100 anno
PRESENTAZIONE CLINICA
• Ipotensione severa
• Ipovolemia clinicamente evidente
• Anomalie ECG o cardiomiopatia
• Paziente esausto e depresso
• Severa mancanza di energie
• Anoressia nausea e vomito
(errato confondimento con malattia GI)
• Mialgia, dolori articolari
• Dolore addominale suggestivo di iniziale peritonite
• Febbre spesso presente
• Stadio avanzato: disturbi cognitivi, sonnolenza, shock ipovolemico
Hahner S. et al. EJE 2010 162 597–602White K. Et al. EJE 2010 162 115–120
ESAME OBIETTIVO –LABORATORIO
• Approfondito esame obiettivo
• Parametri vitali
• ECG
• EGA
• Sodio
• Potassio
• Glicemia
• Emocromo
• Cortisolemia (ACTH)
• PCR
Hahner S. et al. EJE 2010 162 597–602White K. Et al. EJE 2010 162 115–120
DEFINIZIONE DI CRISI SURRENALICA
A) Severo peggioramento delle condizioni generali e almeno 2 dei seguenti segni/sintomi
Ipotensione (sistolica <100 mmHg)
Nausea o vomito
Fatica severa
Febbre
Sonnolenza
Ipoglicemia (> bambini)
Iponatremia (Na < 132 mmoli/l) o Iperkaliemia
B) Somministrazione parenterale di GCs (HC) seguita da miglioramento clinico
GRADING SYSTEM (a seconda del setting necessario per il trattamento e dell’outcome)
Grado 1: gestione ambulatoriale
Grado 2: gestione ospedaliera in reparto generale
Grado 3: unità di terapia intensiva
Grado 4: morte per crisi surrenalica
Hahner S. et al. JCEM 2014
EVENTI PRECIPITANTI CRISI SURRENALICA
• Infezioni, in particolare gastroenteriti
• Interventi chirurgici
• Esercizio fisico intenso, stress emotivo
• Incidenti
• Interruzione di terapia con GCs
Il timing di sviluppo è molto variabile, più rapidamente nei bambini che negli
adulti (range 5 minuti - 7 giorni)
FISIOPATOLOGIA DELLA CRISI SURRENALICA
Permissive Soppressive
GCs
Stimolatorie
Sapolsky RM et al. Endocrine Reviews 2000 21 55–89Besedovsky H et al. Science 1986 233 652–654Barber AE et al. Journal of Immunology 1993 150 1999–2006Webster JC et al. PNAS 2001 98 6865–6870
alterata attivazione e responsività delsistema CV
AI non ancora diagnosticata
Ipotensione
deplezione di volume: Na e della ritenzione di liquidi(mancata azione dei mineralcorticoidi)
manca l’azione soppressiva dell’aumentata secrezione di GCs che previene effetti dannosi di una esagerata difesa immunitaria mediata da citochine pro-infiammatorie
perdita dell’azione permissiva dei GCs sui recettoriadrenergici
FebbreInfezioni
Interazione di GCs e citochinein corso di infezioni maggiori
Interazione di GCs e citochine in corso di infezioni maggiori in A) Soggetti sani B) Pz con AI in terapia sostitutiva standard senza modifiche delle dosi di GCs
La crisi surrenalica si autoamplifica etutti i sistemi lavorano senzacoordinamento a volte non arrestabile
La crisi surrenalica non è mai dovuta alla sola carenza di GCs
La carenza di GCs non è condizionesufficiente per crisi surrenalica ma siverifica dopo l’esposizione a triggers non è prevedibile
CORTISONICI Adulti Idrocortisone (HC) 100 mg e.v. immediatamente, seguito da 200 mg nell’arco delle 24 h (infusione continua e.v. o iniezioni da 50 mg ogni 6 h), poi HC 100 mg/die il giorno successivo
Bambini HC 50 mg/m2 e.v. in bolo,seguito da HC 50–100 mg/m2 nell’arco delle 24 h (infusione continua e.v. o iniezioni ogni 6 h)
Se HC non disponibile: Prednisolone (o Desametasone solo se altri GCs non disponibili)
FLUIDI Adulti SF 0.9% 1000 ml e.v. in infusione rapida nei primi 60 min o SG 5% in isotonica poi infusione salina continua e.v. in base a clinica del pz
Bambini SF 0.9% 20 ml/kg e.v. in bolo rapido da potersi ripetere fino a un totale di 60 ml/kg nella 1° ora poi infusione salina continua e.v. in base a clinica del pz
In base a severità crisi e a pat intercorrenti
Monitoraggio cardiaco, profilassi antitrombotica, antibiotici, ricovero in terapia intensiva
• Generalmente guarigione clinica in 24h • Se non c’è miglioramento considerare altre
cause
TRATTAMENTO
Bornstein S.R: et al. JCEM 2016, 101(2):364 –389
• Il sospetto richiede immediata azione terapeutica, il trattamento precede la conferma biochimica della diagnosi
• Nel sospetto di crisi surrenalica:
Mineralcorticoidi non richiesti se HC > 50 mg/24 h
PREVENZIONE DELLA CRISI SURRENALICA
• dose GCs non hanno l’obiettivo di mimare l’incremento mediano di cortisolo nei soggetti sani durante stress ma di mimare il massimo aumento di cortisolo che si può avere nei soggetti eusurrenalici stressati da tali procedure al fine di coprire necessità inaspettate
• L’eccesso di GCs somministrati a questi pazienti nel breve termine non sembra associarsi a rischi significativi
Udelsman R. et al. Journal of Clinical Investigation 1986 77 1377–1381Salem M. et al.Annals of Surgery 1994 219 416–425
Chirurgia elezioneStress fisico prolungato
rapidi aggiustamenti in risposta a bisogni inaspettati
GESTIONE DELL’ AI IN CONDIZIONI SPECIFICHE - PREVENZIONE DELLA CRISI
Condizione Azione suggerita
Gestione domiciliare della febbre Raddoppiare GCs se TC>38°C o triplicare se > 39°C fino a guarigione (di solito 2-3 gg), aumentare consumo di liquidi con elettroliti
Pz non in grado di tollerare farmaci per o.s. (gastroenterite, trauma o digiuno es. per colonscopia)
Adulti: HC 100 mg i.m.Bambini HC 50 mg/m2 i.m.; età infantile: 25 mg, età scolare 50 mg, adolescenti 100 mg
Stress chirurgico lieve o moderato Adulti: HC 25-75 mg/24h (per 1-2 gg)Bambini: HC 50 mg/m2 o HC dose raddoppiata o triplicata
Chirurgia maggiore con anestesia generale, trauma, parto o patologie che richiedono la terapia intensiva
HC 100 mg e.v. seguito da infusione continua di 200mg/24h (o 50 mg e.v. o i.m. ogni 6h)Bambini: HC 50 mg/m2 e.v. poi 50–100 mg/m2 nell’arco delle 24 h (iniezioni ogni 6 h)
Ridurre il dosaggio e passare a terapia orale quanto prima in base alla clinica
Bornstein S.R: et al. JCEM 2016, 101(2):364 –389
EDUCAZIONE DEL PAZIENTE ALLA GESTIONE DELLA CRISI
• Deve essere rivolta a paziente e familiari
• Aumenta la consapevolezza della propria patologia e nemigliora l’outcome
• Il paziente e i suoi familiari, se ben informati, guidano allagestione più idonea e in tempi più rapidi il personaleparamedico/medico
Il ruolo dello SPECIALISTA:
• Dedicare al paziente il tempo necessario alla spiegazione delle situazionispecifiche e alla gestione delle emergenze/urgenze
• Spiegare il razionale dell’aumento di dose
• Focalizzare l’attenzione sull’educazione del paziente ad ogni controllo(almeno annuale! e indagare la comparsa e modalità di gestione di crisi)
EDUCAZIONE DEL PAZIENTE ALLA GESTIONE DELLA CRISI
Il ruolo del MEDICO DI MEDICINA GENERALE• Gestione del pz nel complesso delle comorbidità• Ruolo essenziale nel supporto alle situazioni di urgenza/ emergenza• Coordinamento del management multidisciplinare
EDUCAZIONE DEL PAZIENTE ALLA GESTIONE DELLA CRISI
Ogni pz dovrebbe portare sempre con se:
•Una steroid emergency card
•Medical alert bracelet or necklace:
“Insufficienza surrenalica – Somministrare cortisonici!”
•Leaflet con informazioni chiare sulle condizioni in cui
aumentare la terapia con GCs in situazioni particolari
o di emergenza
•Un kit di emergenza (idrocortisone 100 mg fiale + siringa ed ago)
utilizzabile da personale paramedico o parenti addestrati
KIT DI EMERGENZA
KIT DI EMERGENZA
KIT DI EMERGENZA
Thanks to all my LAB and CLINICAL Staff:
Mary A. Venneri, Daniele GianfrilliElisa GiannettaCarlotta PozzaEmilia SbardellaRiccardo PofiAlessia CozzolinoValeria HaisenmajerGiulia PulianiTiziana FeolaChiara GraziadioMarianna Minnetti
Sapienza University of Rome – Italy
and Andrea Lenzi