Insufficienza surrenalica: Morbo di Addison

Insufficienza
surrenalica:
Morbo di Addison
06-02-2012
Franco Grimaldi
SOC Endocrinologia e Malattie del Metabolismo
Azienda Ospedaliero Universitaria di Udine
PATOLOGIA SURRENALICA
IPOSURRENALISMI
ASSE IPOTALAMO-IPOFISI-SURRENE
IPOTALAMO
CRH
\
IPOFISI
ACTH
CORTISOLO
SURRENE
MORBO DI ADDISON: aspetti clinici
1) Colpisce individui di qualsiasi età
2) Eziopatogenesi più frequente legata a cause
idiopatiche e/o autoimmuni. In passato la causa
più frequente era la tubercolosi.
3) Perdita di peso, perdita di forza , colore
bronzino della cute. Se non trattato porta a
disidratazione, ipotensione e stati di shock
specie se il paziente viene sottoposto a stress
fisici( es. infezioni)
4) Il colorito bronzino della cute appare legato agli
elevati livelli di ACTH per perdita del feedback
ipofisario.
Patologia Surrenalica Infettiva
TUBERCOLOSI
• In passato risultava la causa più
frequente di M. di Addison.
• Aumento delle ghiandole bilateralmente
spesso associata a calcificazioni
• Pattern istologico differente da quello
tipico tubercolare: necrosi caseosa con
ridotta reazione granulomatosa.
Patologia Surrenalica Infettiva
INFEZIONI VIRALI
1) Herpes simplex neonatale con necrosi
ed inclusioni eosinofile Cowdry A
evidenti nel surrene e fegato.
2)Cytomegalovirus
neonatale
con
coinvolgimento multiorgano e tipiche
inclusi nucleari e citoplasmatiche
3) Sindromi da immunodeficit acquisiti
SINDROME DI WATERHOUSEFRIEDERICHSEN (WFS)
DEFINIZIONE: Forma di shock
settico associata a shock vascolare,
CID ed emorragia surrenalica.
•
•
•
•
SINDROME DI WATERHOUSEFRIEDERICHSEN (WFS): ASPETTI CLINICI
Origine associata soprattutto ad infezioni
batteriche
Spesso fatale
La CID si associa di frequente a petecchie
cutanee.
L’emorragia
surrenalica
appare
solitamente secondaria alla carenza di
fibrinogeno
Definition of the Autoimmune
Polyglandular Syndrome (APS)
…..as the coexistence of multiple
autoimmune glandular failure or best
(of multiple autoimmune diseases)
in a patient.
Neufeld and Blizzard 1980
CLASSIFICATION OF APS
APS-1 (APECED)
Whitaker’s syndrome
Chronic candidiasis
Hypoparathyroidism,
Addison’s disease (at least two)
APS-2
(Schimdt’s syndrome or
Carpenter’s syndrome)
Addison’s disease (always present)
+
thyroid autoimmune diseases and/or Type 1
diabetes mellitus
APS-3
(Thyro-gastric syndrome)
Thyroid autoimmune diseases
+
other autoimmune diseases (escluding: Addison’s)
APS-4
Combinations not included in the previous groups
Neufeld and Blizzard 1980
APS-2 (Schmidt’s syndrome)
Addison’s disease
+
Thyroid autoimmune diseases
and/or
Type 1 DM
+
other minor autoimmune diseases
FREQUENCY
15-40 cases / million
APS-2
Combinazione Familiare
Madre
T. Hashimoto
Figlia
M. di Addison
Chronic Hypoparathyroidism (CH)
General features
• CH is the first endocrine
disease to occur
•
Manifestazioni cliniche
•tetania
•convulsioni
•disturbi psichiatrici
•scompenso cardiaco reversibile
•cataratta sottocapsulare
•QT prolungato
In neonatal period it is
important to distinguish
CH from genetic forms:
-Di George’s syndrome
-Kenney-Caffey’s syndrome
Segno di
Trousseau
(tetania latente)
-Barakat’s syndrome
Pathology
• Parathyroid tissue from
patients with CH is
atrophic
with
a
lymphocytic
infiltration
but
frequently
the
parathyroid tissue is not
detectable
McIntyre Gass,
Am J Ophtalmol 54:660;1962
Q-T prolungato, alterazioni ST
Calcificazioni sublenticolari
Calcificazioni sublenticolari
Addison’s disease is the second endocrine disease to appear
Pathology and imaging
The adrenal glands from patients
with AD is atrophic with lymphocytic
infiltration but sometimes the
adrenal tissue is not detectable
Insufficienza
corticosurrenalica
Cronica
Primitiva=Morbo di Addison, per distruzione o disfunzione
della corticale del surrene
Femmina:Maschio=2.6:1; Frequente nella 3a-5a decade di vita
Secondaria per inefficace produzione di ACTH
Acuta
cause di insufficienza surrenalica
Autoimmune
primitiva
Tumori maligni e metastasi
Emorragia surrenalica
Infettive
tubercolosi, citomegalovirus, micosi (candida), AIDS
Adrenoleucodistrofia
Patologie infiltrative
amiloidosi, emocromatosi, sarcoidosi
Iperplasia surrenale congenita
Farmaci
ketoconazolo, metirapone, aminoglutetimide, mitotane, etomidato
Segni e sintomi
Difetto di cortisolo
Stanchezza
Affaticamento
Anoressia, perdita di peso
Nausea
Vomito
Ipotensione
Iponatriemia
Ipoglicemia
Iperpigmentazione
Difetto di mineralcorticoidi
Disidratazione
Ipotensione
Iponatriemia
Iperpotassiemia
Acidosi
Iperpigmentazione: generalizzata, ma più evidente in aree esposte al sole,
aree di pressione, pieghe, cicatrici, mucosa orale e gengive
Iperpigmentazione: mucosa orale e gengive
Vitiligine
• Collo, torace, ascella
• Maggiore iperpigmentazione sul
bordo delle aree depigmentate
Crisi Addisoniana
Ipotensione e shock
Febbre
Disidratazione
Nausea e vomito
Anoressia
Dolori addominali
Stanchezza
Apatia
Attività mentale depressa
Ipoglicemia
Insufficienza
corticosurrenalica
Cronica:
 Primitiva: Morbo di Addison, per distruzione o
disfunzione della corticale del surrene
 Secondaria per inefficace produzione di ACTH
Insufficienza surrenalica
secondaria
Mancanza di iperpigmentazione per bassi livelli di ACTH
Assenza dei sintomi correlati a deficit di mineralcorticoidi
Storia di terapia con glucocorticoidi (malattie
autoimmuni, allergie)
Quandro cushingoide (iatrogeno)
Tumori della regione ipotalamo-ipofisaria
Associazione con altri segni e sintomi di deficit anteroipofisario e/o
diabete insipido
IPOSURRENALISMI
SINTOMI
NEL 65-50 % DEI CASI
 IPERKALIEMIA
 IPERAZOTEMIA
IPOSURRENALISMI
SINTOMI
IPOSURRENALISMI
DIAGNOSI
ADRENAL FAILURE
THERAPY
Allolio. Lancet;361:1881, 2003
GENERAL PRINCIPLES
RULES
- mineralcorticoid
deficiency
- mineralcorticoid substitutive
therapy
- daily production of cortisol
6 mg/m2/daily (12-15)
- smaller doses: hydrocortisone
20 mg/daily (30)
- circadian rythm
- fractionated doses: 3/4 + 1/4
1/2 + 1/4 + 1/4
OVER-REPLACEMENT WITH STANDARD DOSE
bone
glucose metabolism
intraocular pressure
mortality in hypopituitaric patients ?
Peacey. Clin Endocrinol;46:255, 1997
Wichers. Clin Endocrinol;50:759, 1999
ADRENAL FAILURE
THERAPY
Plasma half life, duration of action, glucocorticoid and mineralocorticoid potencies and
equivalent doses of some commonly used glucocorticoid preparations and of
fludrocortisone
Relative potency
Replacement
dose (mg)
Steroid
(min)
Duration of
action (h)
Cortisol
80
8 - 12
1.0
1.0
20
Cortisone
30
8 - 12
8.0
0.8
25
Prednisone
60
12 - 36
3.5-4.0
0.8
5
Prednisolone
200
12 - 36
4.0
0.8
5
Methylprednisolone
200
12 - 36
5.0
0.5
4
Triamcinolone
200
12 - 36
5.0
0.0
4
Dexamethasone
300
36 – 72
30.0
0.0
0.5
Betamethasone
300
36 - 72
30.0
0.0
0.5
Fludrocortisone
240
12 - 24
10.0
125.0
2
Half-life
Glucocortic Mineralocortic
Trattamento sostitutivo steroideo
Farmaco
Posologia/die
Durata di
Potenza relativa
Cross-reazione
azione
Na-riten. Antiinfia.
Idrocortisone
20 mg
1
1
Breve
100%
Cortisone
acetato
37.5 mg
0.8
0.8
Breve
0.24%
Prednisone
7.5 mg
0.8
4
Intermedia
1.5%
Desametazone
0.75 mg
0
25
lunga •'
0.00%
Fludrocortisone: Florinef cp 0.1 mg
Trattamento sostitutivo steroideo
– L'aggiustamento della dose deve essere effettuata sui sintomi
clinici, il livello degli elettroliti ed il controllo della PA
– è necessaria la sostituzione con mineralattivi (fludrocortisone
acetato 0.05-0.1 mg/die)
– Il sovradosaggio deve essere evitato
– La dose abituale deve essere incrementata (25-100% condizioni di
stress
– Episodi ripetuti di vomito possono richiedere un trattamento
parenterale (es. desametazone 4 mg im)
– Nella fase peri e post-chirurgica il trattamento abituale per os
deve essere sostituito con quello parenterale (es. idrocortisone
100 mg ogni 4-6 ore nei liquidi di idratazione)
Therapeutic management of adrenal insufficiency
Cortisol day curves in patients with adrenal insufficiency receiving a daily
hydrocortisone dose of 20 mg (15–5–0 mg) and in healthy subjects.
Best Practice & Research Clinical Endocrinology & Metabolism 23 (2009) 167–179
Therapeutic management of adrenal insufficiency
Mineralocorticoid replacement
Aldosterone has a key role in water and
electrolyte homeostasis.
Principal stimulators of aldosterone synthesis
and secretion are angiotensin II and
potassium.
Aldosterone shows only slight diurnal
variation.
Mineralocorticoid replacement is
only necessary in patients with
as
primary adrenal insufficiency,
in secondary adrenal insufficiency
the
rennin-angiotensin-system
remains
unaffected.
As the half-life of aldosterone in the
circulation is relatively short, the synthetic
mineralocorticoid fludrocortisone is used.
Fludrocortisone is given as a single
morning dose of 0.05–0.2 mg.
It
has
been
estimated
that
the
mineralocorticoid potency of 20 mg
hydrocortisone is equivalent to 0.05 mg
fludrocortisone
Treatment
surveillance
comprises
measurement of blood pressure sitting and
erect (with a postural drop >20 mmHg
indicating
under-replacement),
serum
sodium, serum potassium and plasma renin
concentration (PRC).
The most sensitive parameter for monitoring
an adequate mineralocorticoid replacement
is measurement of the PRC.
Target level is a PRC within the upper normal
range.
In cases of increased loss of fluid and
electrolytes, e.g. heat, patients may require
higher fludrocortisone doses.
If
arterial
hypertension
occurs,
fludrocortisone dose reduction should be
considered
Best Practice & Research Clinical Endocrinology & Metabolism 23 (2009) 167–179
Therapeutic management of adrenal insufficiency
DHEA treatment exerts
positive effects on mood,
sexuality and subjective
health status in patients
with chronic adrenal
insufficiency
Spider plots showing the eight dimensions of health assessed by the short form
36 (SF-36) questionnaire
at baseline, 6 months, 12 months, and after washout in DHEA (left panel) or
placebo-treated (right panel) groups indicating moderately improved wellbeing in patients receiving DHEA replacement
Best Practice & Research Clinical Endocrinology & Metabolism 23 (2009) 167–179
Therapeutic management of adrenal insufficiency
Prevention and management of adrenal crisis
Under conditions of minor physical
stress (e.g. fever, cold, surgery
under
local
anaesthesia)
the
hydrocortisone dose has to be
increased to 30–50 mg/day or, as a
general rule, replacement doses
should be doubled or tripled until
recovery (usually 3–4 days).
In case of major physical stress (e.g.
major
surgery
with
general
anaesthesia, trauma, delivery or
diseases that require intensive care)
we suggest a dose regimen of 150 mg
hydrocortisone in 5% glucose as a
continuous infusion over the first 24
hours, with reduction to 100 mg
hydrocortisone/day intravenously the
following day.
Management of acute adrenal crisis
consists of immediate intravenous
administration
of
100
mg
hydrocortisone followed by 100–200
mg intravenously per 24 h and
continuous infusion of larger
volumes of physiological saline
solution (initially 1 L/h) under
continuous cardiac monitoring.
However, steroid replacement must
be started immediately without
waiting for the results of hormone
measurements, as it is far safer to
administer hydrocortisone for a few
days to patients with intact adrenal
function than to delay life-saving
hydrocortisone administration in
adrenal crisis.
Best Practice & Research Clinical Endocrinology & Metabolism 23 (2009) 167–179