Family Nurse Practitoner Concept Map
Addison's Disease
Pathophysiology
Adrenal cortex is under the control of two
different regulatory circuits: HPA axis and
the renin-angiotensin- aldosterone system
(RAAS) (Hahner et al., 2021).
Circadian and stress inputs converge on the
hypothalamus's paraventricular nucleus
(PVN), inducing the release of corticotropin-
releasing hormone (CRH) and arginine
vasopressin (Hahner et al., 2021).
CRH stimulates adrenocorticotropic
hormone ACTH release, inducing secretion of
corticosteroids, mainly cortisol, but also
dehydroepiandrosterone (DHEA) and aldosterone
(Hahner et al., 2021). The HPA axis is
regulated by cortisol via feedback regulation in the hypothalamus and pituitary (Hahner et al.,
2021). Glucocorticoid
deficiency leads to a loss of the negative
feedback of cortisol on the hypothalamus and pituitary, resulting in
increased CRH and ACTH levels (Hahner et
al., 2021). Decreased aldosterone
secretion results in increased renin (>4.1ng/ mL/hr) release from the kidney (Gomella, 2022;
Hahner et al, 2021).
Autoimmune destruction of
adrenocortical tissue is caused by
autoantibodies, most frequently autoantigen, 21-hydroxylase (Hahner
et al., 2021).
Circulating CD4+ and CD8+ T cells with
autoreactivity against 21-hydroxylase, and
with contributions from dendritic cells and
macrophages, mediates destruction of the
adrenal cortex (Hahner et al., 2021).
Activation of B cells in local draining lymph
nodes leads to the production of
autoantibodies against the enzyme 21
hydroxylase (Hahner et al., 2021).
Circulating CD4+ and CD8+ T cells targeting
21-hydroxylase- expressing
corticotrophs mediate the destruction of the
adrenal cortex (Hahner et al., 2021).
Environmental factors not known, but viruses
might be involved (Hahner et al., 2021).
Addison's disease is associated with major
histocompatibility complex (MCH)
genotypes such as DR3- DQ2 and DrR4-DQ8. Variants in CTLA4, PTPN22, CIITA, and
CLEC16A (Hahner et al., 2021).
The heritability of Addison disease is high
(Hahner et al., 2021).
Lack of aldosterone leads to loss of sodium
in the body, with decreased intravascular
fluid volume and hypotension (Hahner et
al., 2021).
Loss of negative feedback by cortisol results in increased
release of pro- opiomelanocortin and pro-opiomelanocortin- derived peptides such
as ACTH and alpha melanocyte simtulating hormone (alpha- MSH) (Hahner et al., 2021).
Increase in alpha MSH levels lead to skin
hyperpigmentation through stimulation of MSHR (or melanocortin recetpor 1) in areas of the body exposed to
sun but also in areas of increased mechanical
friction (palmar creases, scars, groin and oral
mucosa) (Hahner et al., 2021).
Gradual adrenocortical destruction results in
decreased adrenal glucocorticoid reserve
(Tobias & Hammer, 2018).
Basal Secretion is normal but does not
increase in response to stress or surgery
(Tobias & Hammer, 2018).
Stress, surgery, trauma or infection can
precipitate an acute adrenal crisis (Tobias &
Hammer, 2018).
With further loss of Cortical tissue, basal
secretion of glucocorticoids and mineralocorticoids becomes deficient, leading to clinical manifestations of chronic adrenal
insufficiency (Tobias & Hammer, 2018),
Fall in plasma cortisol reduces the feedback inhibition of pituitary ACTH secretion, and plasma level of ACTH
rises (Tobias & Hammer, 2018).
All adrenocortical zones are affected, resulting
in a deficiency of all adrenocortical
hormones (Hahner et al., 2021).
DHEA secretion is impaired due to the
zona reticularis's destruction, leading to
adrenal androgen deficiency (Hahner et
al., 2021).
Adrenal Crisis (Hahner et al., 2021).
A potentially fatal condition caused by
acute cortisol deficiency (Hahner et al., 2021).
The imbalance between the demand and
availability of glucocorticoids (Hahner
et al., 2021).
Modified immune response owing to lack
of glucocorticoid- mediated
immunomodulation leads to increased
inflammatory cytokines, further
activating pro- inflammatory pathways
(Hahner et al., 2021).
Cortisol deficiency is further aggravated by
cytokine-induced glucocorticoid receptor resistance (Hahner et
al., 2021).
Cortisol deficiency reduces blood vessel
responsiveness to catecholamines,
aggravating the volume depletion caused by
aldosterone deficiency (Hahner et al., 2021).
Cortisol deficiency results in impaired
mobilization of energy owing to reduced
hepatic gluconeogenesis, reduced muscular
amino acid liberation and reduced production of fatty acids (Hahner et
al., 2021),
Physical exam
Hypothalamic-pituitary disease can lead to
manifestations due to the invovlement of
other endocrine axes (thyroid, gonad, Gh, prolactin) or visual impairment with
bitemporal hemianopia caused by chiasmal compression (Arlt,
2022).
Weight loss in adults (Saverino & Falorni,
2020).
Profound asthenia (Saverino & Falorni,
2020).
Mental Depression (Tobias & Hammer,
2018).
Oligo-amenorrhea secondary to adrenal androgen deficiency (Saverino & Falorni,
2020).
Mineralocorticoid defciciency (Arlt, 2022).
Dizziness, orthostatic hypotension (Arlt,
2022).
Abdominal pain, nausea, vomiting (Arlt,
2022).
Hyponatremia (<135meq/L) (Arlt, 2022;
Gomella, 2022).
Increased serum creatinine (0.7-1.3mg/
dL) due to volume depletion (Arlt, 2022;
Gomella, 2022).
Low blood pressure (<120/80 mmHg) (Arlt, 2022; Gomella, 2022)
Hyperkalemia (>5 meq/ L) (Arlt, 2022; Gomella,
2022)
Salt Craving (Artl, 2022).
Hypochloremic (<98 meq/L) acidosis (Gomella, 2022;
Saverino & Falorni, 2020),
Elevated BUN >20mg/dL (Betterele et al., 2019;
Gomella, 2022).
hypercalcemia- >10.6mg/dL. Decreased
intestinal absorption and decreased
excretion of calcium (Betterele et al., 2019;
Gomella, 2022; Saverino & Falorni, 2020).
Dehydration (Allen, 2023).
Low aldosterone (<12ng/dL supine; <17ng/dL upright)
(Allen, 2023; Gomella 2022).
Reduction in axillary and pubic hair (Saverino
& Falorni, 2020). Sleep disturbances secondary to supra physiologic cortisol levels (Saverino &
Falorni, 2020). Irritability and inability
to concentrate (Saverino & Falorni,
2020). Clinical signs of other
associated autoimmune diseases (thyroid/
vitiligo) (Saverino & Falorni, 2020).
Headaches (Saverio & Falorni, 2020).
Hypersensitivity to tastes and smells
(Saverino & Falorni, 2020).
Adrenal Crisis (Tobias & Hammer, 2018).
Anorexia, nausea, and vomiting (Tobias &
Hammer, 2018).
Acute abdomen: abdominal tenderness,
fever (Arlt, 2022).
Volume depletion and dehydration (Tobias &
Hammer, 2018). Hypovolemic shock
(Arlt, 2022).
Decreased responsiveness, stupor,
coma (Arlt, 2022).
Dry and itchy skin (Hahner et al., 2021).
Loss of libido in women (Hahner et al., 2021).
Hyperpigmentation of skin, mucosa (Tobias &
Hammer, 2018).
Glucocorticoid deficiency (Arlt, 2022).
Occasional hypoglycemia- more
often in children (Arlt, 2022).
Normocytic anemia, lymphocytosis,
eosinophilia (Arlt, 2022),
Lethargy (Arlt, 2022).
Joint pain (Arlt, 2022).
Easy fatigability (Arlt, 2022).
Anorexia/weight loss( Arlt, 2022).
Slightly increased TSH due to loss of feedback
inhibition of TSH release (Arlt, 2022).
Fever (Arlt, 2022).
Hypoglycemia (Allen, 2023).
Adrenal insufficiency in children (Hahner et al.,
2021).
Failture to thrive (Hahner et al., 2021).
Recurrent infections (Hahner et al., 2021).
Family history of neonatal deaths or
early postnatal deaths (Hahner et al, 2021).
Ambiguous genitalia at birth (Hahner et al,
2021).
Diagnostics
Usually diagnosed after years of non-specific symptoms: fatigue,
poor well-being, postural dizziness,
nausea, and weight loss (Hahner et al., 2021).
Treatment should not be delayed by
performing diagnostic procedures (Hahner et
al., 2021).
Mass spectrometry analysis detects lower cortisol concentrations
and has enhanced specificity (Hahner et
al., 2021).
Plasma ACTH (Hahner et al., 2021).
Morning serum cortisol <140nmol/L or < 5
micrograms/dL (Hahner et al., 2021).
ACTH1-24 stimulation test (synacthen tet/
corticotropin- stimulation test
(Hahner et al., 2021).
250 micrograms dose of ACTH 1-24 IV or IM to
asses proper functioning of adrenal glands (Hahner et al.,
2021).
Peak serum cortisol concentration of < 450
nmol/l 30 minutes after ACTH stimulation or a
peak concentration of < 500nmol/L 60 minutes after ACTH stimulation establishes a positive
diagnosis (Hahner et al., 2021).
< 18mcg/dL cortisol or NO response . Patient's have low 08:00 cortisol
levels, high ACTH (normal is 9-52 pg/mL)
and virtually no increase in plasma
cortisol after cosyntropin ( Munir et
al., 2024; Tobias & Hammer, 2018).
Once Addison's disease diagnosis is established,
the patient should be evaluated for the
presence of 21- hydroxylase
autoantibodies in the serum by indirect
immunofluroesecence (Hahner et al., 2021; Saverino & Falorni,
2020).
CBC, serum NA, K, Creatinine, urea, TSH .
Urea, creatinine, calcium and potassium
are increased (Arlt, 2022; Bertterle et al.,
2019).
+ 21-hydroxylase autoantibodies, the
patient should be screened for concomitant autoimmune
comorbidity (Hahner et al., 2021).
A negative antibody test, CT scan of adrenals is recommended to rule
out inflammatory processes or
destruction of adrenals by hemorrhage,
infiltration or metastases of extra-
adrenal cancer (Hahner et al., 2021).
Men with negative 21- hydroxylase
autoantibodies, adrenoleukodystrophy should be ruled out by measuring long-chain fatty acids in serum (Hahner et al., 2021).
Rule out TB and HIV (Hahner et al., 2021).
CXR to rule out TB Serum 17OHP to rule
out congenital adrenal hyperplasia (Arlt, 2022).
TB- chest x-ray demonstrates
cavitations, adrenal enlargement with calcifications, and
positive test indicating previous contact with a bacillus (Betterle et al.,
2019).
Hyperdense adrenals suggest
hemochromatosis, order specific genetic testing (Betterle et al.,
2019).
Patients with history of cancer and CT scan of
adrenals reveals bilateral adrenal
masses, an ultrasound- guided or CT-guided fine needle aspiration
biopsy may be necessary to define the diagnosis (Betterle et
al., 2019).
+ 21- hydroxylase autoantibodies:
Autoimmune adrenalitis autoimmune
polyglandular syndrome (APS) (Arlt,
2022).
Combined renin and aldosterone levels to
determine mineralocorticoid
efficiency indicated by low-normal aldosterone
in the presence of increased renin levels (Hahner et al., 2021).
Serum cortisol (Hahner et al., 2021).
Morning cortisol of < 140nmol/l or <5
micrograms/dL in combination with
increased ACTH levels, twice the upper normal
limit (9-52 pg/mL), is confirmative (Hahner et
al., 2021; Munir et al., 2024).
Prevalence of the disease Addison's
disease
Prevalence in Western societies of about 100-140 cases per
million (Barthel et al., 2019).
Prevalence in Europse has been increasing
over time (Betterle et al., 2019).
Europe: 9-22 new cases per 100,000 population
(Hahner et al., 2021).
Japan: 5 cases per million inhabitants/year
(Severino & Falorni, 2020).
Germany: 4-6 cases per million per year
(Barthel et al., 2019). Norway: 6 new cases/
million inhabitants/year (Saverino & Falorni,
2020).
22 cases per 100,000 population in Iceland (Hahner et al., 2021).
More prominent in Women than in men,
with peak incidence in the third decade of life
(Hahner et al., 2021). Congenital Adrenal Hyperplasia (CAH)
varies between populations, ranging
from 0.5 to 1 person per 10,000 population
(Hahner et al., 2021) Higher frequencies in individuals with other autoimmune disorders
than in the general population (Hahner et
al., 2021).
U.S.: 0.6 per 100,000 population annually (Munir et al., 2024).
Half of the cases are acquired, mostly caused
by autoimmune destruction of the
adrenal glands; the other one half are
genetic mostly commonly caused by
distinct enzymatic blocks in adrenal steroidogenesis
affecting glucocorticoid synthesis (Arlt, 2022).
Hypothalamic-pituitary origin of disease with
prevalence of 3 in 10,000 (Arlt, 2022).
Primary adrenal insufficiency has a prevalence of 2 in 10,000 (Arlt, 2022).
Addison's disease presentation 30-50
years old (Munir et al., 2024).
More frequent in women (Munir et al.,
2024).
90% of non -Congenital Adrenal Hyperplasia
(CAH) in industrialized countries (Hahner et al.,
2021).
Infections are predominant cause of
Primary Adrenal Insufficiency (PAI) in
regions with high prevalence of
tuberculosis, HIV infection and
opportunistic infections (Hahner et al., 2021).
Manifests between 20-50 years of age, but can occur at any age,
and onset rare in children <2 years of age
(Hahner et al., 2021).
1.4 cases per 100,000 population in South Africa (Hahner et al.,
2021).
Risk Factors
Primary adrenal insufficiency or
Addison's disease (Tobias & Hammer,
2018).
Autoimmune: 80% (Tobias &
Hammer, 2018).
anti-adrenal antibodies 80% patients with
autoimmune adrenal insufficiency (Tobias &
Hammer, 2018).
adrenal cortex antibodies ACAs (Tobias
& Hammer, 2018).
21 hydroxylase antibodies (Tobias &
Hammer, 2018).
Isolated autoimmune adrenalitis 30-40% (Arlt,
2022).
Autoimmune Polyglandular
syndromes APSs 60-70% (Arlt, 2022).
Autoimmune polyendocrine
syndrome type 2 APS-2 Halotypes hLA-B8 (DW3)
and DRE polygenic inheritance (Arlt, 2022;
Tobias & Hammer, 2018).
Coincident autoimmune diseases: thyroid
autoimmune disease, vitiligo, premature
ovarian failure, Type 1 DM, pernicious anemia
(Arlt, 2022).
autoimmune polyendocrine
syndrome type 1 (APS1) autosomal recessive disorder caused by
mutation in autoimmune regulator
(AIRE) with onset in childhood (Arlt, 2022).
Amyloidosis (Tobias & Hammer,
2018).
Sarcoidosis (Tobias & Hammer, 2018).
Hemochromatosis (Tobias & Hammer,
2018),
Metastatic carcinoma/ lymphoma (Non-
Hodgkins) (Tobias & Hammer, 2018).
Radiation therapy (Tobias & Hammer, 2018).
Antiphospholipid syndrome (Tobias &
Hammer, 2018). Adrenal
Hemorrhage and Infarction (Tobias & Hammer, 2018).
Pseudomonas septicemia in children
(Tobias & Hammer, 2018).
Adults: sepsis (Tobias & Hammer, 2018).
Adrenal vein thrombosis (Tobias &
Hammer, 2018).
Severe burns (Tobias & Hammer, 2018).
Traumatic shock (Tobias & Hammer, 2018).
Obstetric complications (Tobias & Hammer,
2018).
Waterhouse - Friderichsen syndrome
in children (Tobias & Hammer, 2018).
Abdominal Surgery (Tobias & Hammer,
2018).
HIV/AIDS Opportunistic infections -clinical
adrenal insufficiency in less than 5% AIDS patients (Tobias &
Hammer, 2018).
Cytomegalovirus (Tobias & Hammer,
2018).
Disseminated Mycobactterium avium- intracellulare (Tobias &
Hammer, 2018).
Cryptococcus neoformans (Tobias &
Hammer, 2018)
Pneumocystis jirovecii (Tobias & Hammer,
2018).
Toxoplasma gondii (Tobias & Hammer,
2018).
Kaposi Sarcoma (Tobias & Hammer, 2018).
Congenital defects (Tobias & Hammer,
2018).
X-linked adrenoleukodystrophy
(Tobias & Hammer, 2018).
Enzyme defects: enzymatic blocks in
adrenal steroidogenesis affecting glucocorticoid
synthesis (CAH) (Alrt, 2022; Tobias & Hammer,
2018).
Adrenal hypoplasia (Tobias & Hammer,
2018).
Familial glucocorticoid deficiency (FDG) (Tobias
& Hammer, 2018).
FDG type 1: resistance to ACTH caused by mutations within
coding region of the ACTH receptor MC2R (Tobias & Hammer,
2018).
FDG type 2 ACTH receptor accessory
protein (MRAP) mutation/dysfunction
(Tobias & Hammer, 2018).
FDG type 4 mutations in nicotinamide
nucleotide transhydrogenase
(NNT) (Tobias & Hammer, 2018).
Tuberculosis (Tobias & Hammer,
2018).
Drugs (Tobias & Hammer,
2018).
Metyrapone (Tobias & Hammer, 2018).
Aminoglutethimide (Tobias & Hammer,
2018).
Trilostaine (Tobias & Hammer, 2018).
Ketoconazole (Tobias & Hammer, 2018).
suramin (Tobias & Hammer, 2018).
Etomidate (Tobias & Hammer, 2018).
Surgical adrenalecotmy (Tobias & Hammer,
2018).
Granulomatous infections (Tobias &
Hammer, 2018).
Histoplasmosis (Tobias & Hammer, 2018).
Coccidioidomycosis (Tobias & Hammer,
2018). Cytotoxic and
chemotherapeutic agents (Tobias & Hammer, 2018).
mitotaine (Tobias & Hammer, 2018).
megestrol (Tobias & Hammer, 2018).
mifepristone (Tobias & Hammer, 2018).
Secondary adrenal insufficiency (Tobias &
Hammer, 2018).
Chronic exogenous glucocorticoid therapy
(Tobias & Hammer, 2018).
Pituitary tumor (Tobias & Hammer, 2018).
Hypothalamic tumor (Tobias & Hammer,
2018).
Acquired hypothalamic isolated CRH deficiency
(Tobias & Hammer, 2018).
Morbidity and Mortality
Adrenal crisis is an acute complication and
major cause of death (Saverino & Falorni,
2020).
Precipitated by GI infection, fever,
surgery, strenuous physical activity,
cessation of glucocorticoid therapy,
psychic distress (Saverino & Falorni,
2020).
GI infections may lead to inability to ingest
and absorb oral hydrocortisone which
can lead to adrenal crisis (Tobias & Hammer, 2018).
47% patients with Autoimmune Addison's
Disease (ADD) require at least one
hospitalization for an adrenal crisis after
diagnosis (Saverino & Falorni, 2020).
Disruption of their activities of daily life (Hahner et al., 2021).
Women globally have lower fertility and parity (Saverino &
Falorni, 2020).
Premature ovarian failure with
hydrocortisone treatment (Arlt, 2022).
Fertility affected after Addison's diagnosis (Saverino & Falorni,
2020).
Mortality rate of 0.5/1000 patients
(Barthel et al., 2019).
Reduced vitality, increased fatigue and anxiety (Hahner et al,
2021). Osteoporosis and hyperglycemia secondary to
Hydrocortisone treatment (Saverino &
Falorni, 2020).
Reduced quality of life secondary to lack of
circadian and ultradian cortisol tissue exposure
(Hahner et al, 2021). Pregnant women: increased risk of preterm delivery,
cesarean section, and fetal growth restriction
(Saverino & Falorni, 2020).
Post-Partum complications: wound
complications, infections, the need of a
transfusion, venous thromboembolic
disease, prolonged hospital stays (Saverino
& Falorni, 2020).
Glucocorticoid effect on the cardiovascular
system: Hypertension, salt and water
retention, increased potassium excretion.
High-dose hydrocortisone
contributes to changes in body weight and
premature cardiovascular deaths
(Saverino & Falorni, 2020).
Risk of fragility fractures related to cortisol deficiency, DHEA deficiency,
hyponatremia, loss of body weight, asthenia,
reduced muscular activity, increased propensity to fall,
melanodermia-induced vitamin D insufficiency
(Saverino & Falorni, 2020).
Sleep disturbances associated with
physiologic cortisol levels (Saverino &
Falorni, 2020).
Treatment
Lifelong substitutive treatment with
hydrocortisone (HC) or cortisone acetate when
HC is not available (Saverino & Falorni,
2020).
15-25mg of HC/day. The half life of HC is 90
minutes, requiring 2-3 daily doses to mimic physiologic circadian
pattern of cortisol (Saverino & Falorni,
2020).
Half to two thirds of total daily dose of HC
should be administered in the morning at waking and the
remaining doses given every 6 hours, with the smallest dose no later
than 6 hours before bedtime (Saverino &
Falorni, 2020).
For adjustmen of HC dose, use clincial
paratmeters such as: patient's well-being,
body weight, waist-hip circumfernece ratio,
blood pressure, sodium and potassium levels (Saverino & Falorni,
2020).
Insufficient hydrocortisone doses: fatigue, weight loss,
nausea, aand may lead to adrenal crisis
(Hahner et al., 2021).
High hydrocortisone excess: Cushing's
syndrome: weight gain, increased abdominal
fat, buffalo hump, thin skin, easy bruising,
hypertension, and Type 2 DM (Hahner et al,
2021).
Autoimmune process is destroying the total
adrenal cortex, patients also require
mineralocorticoid therapy with 50-200 micrograms/day of fludrocortisone once daily in the morning (Saverino & Falorni,
2020).
Treatment evaluated by measuring blood
pressure, sitting and standing, to detect
postural drop indicative of hypovolemia.
Monitor Serum sodium, potassium , and plasma
renin regularly (Arlt, 2022).
Adrenal Crisis treatment (Hahner et
al, 2021).
Hydrocortisone 100mg IV or IM bolus injection followed by continuous IV infusion of 200mg of
Hydrocortisone/24 hours (Hahner et al,
2021).
or 50mg IV/IM Hydrocortisone every 6 hours (Hahner et al., 2021).
After initial treatment period and recovery of
patient, Hydrocortisone dose tapered in line
with clinical response, close monitor of BP and symptoms (Hahner et
al., 2021).
IV glucose may be needed, particularly in children (Hahner et al.,
2021).
Transfer to oral hydrocortisone within
24 hours if possible (Hahner et al., 2021).
Isotonic Saline IV fluids under tight monitoring
to avoid too-rapid correction of
hyponatremia (Hahner et al., 2021).
Treat precipitating cause of adrenal crisis (Hahner et al., 2021).
Adrenal androgen replacement is an
option for patients with lack of energy, despite
optimized glucocorticoid and mineralocorticoid
replacement. May be indicated in women
with features of androgen deficiency, loss of libido. DHEA
25-50 mg DHEA (Arlt, 2022).
Treatment monitored by measurement of
DHEAS, androstenedione,
testosterone, and sex hormone binding globulin (SHBG) 24 hours after the last
DHEA dose (Arlt, 2022).
Hydrocortisone 30mg or more will affect bone health, patients need regular bone mineral
density evaluation (Arlt, 2022).
Stress related glucocorticoid dose
adjustments, doubling the routine oral
glucocorticoid dose in case of intercurrent illness (Arlt, 2022).
All patients should carry a hydrocortisone
self-injection emergency kit in
addition to their steroid emergency cards and bracelets (Arlt, 2022).