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).