Introduction – Addison’s disease
Primary adrenal insufficiency.
The completely dominant cause of Addison’s disease is autoimmunity in the form of adrenalitis, which may be isolated or part of autoimmune polyglandular disease.
Unusual causes include:
- Malignancy (usually metastases)
- Bleeding (NOAC, Warfarin)
- Fungal infections
- Granulomatous diseases
- Tuberculosis, especially in developing countries
Prevalence has been estimated at 93-140 per one million individuals.
The onset of illness usually occurs between the ages of 20-40, but can also occur earlier and later in life.
Symptoms and Clinical Signs – Addison’s disease
- Acute adrenal cortex failure is a life-threatening condition that requires prompt treatment!
- Fatigue, general weakness, low blood pressure, emaciation, and hyperpigmentation may be present for a long time. During an Addison crisis, abdominal symptoms such as pain, nausea, and vomiting often occur. Cravings for salty food are common.
- Low S-Na, elevated S-K, sometimes slight creatinine increase and hypoglycemia. Elevated TSH and hypercalcemia can sometimes be seen.
- Keep in mind that Addison’s disease often becomes manifest in conjunction with other acute illnesses, such as infection.
- Addison’s disease often occurs in conjunction with other autoimmune diseases, such as type 1 diabetes mellitus, hypothyroidism, and pernicious anemia.
- Acute abdomen
- Diabetes mellitus
Diagnostics – Addison’s disease
- Baseline testing:
– CBC (Hb, WBC, PLT, diff)
– Electrolytes (Na, K, Crea)
– Liver panel (ASAT, ALAT, ALP, bilirubin)
– Calcium and albumin
– Thyroid tests (TSH and free T4)
– B12/folic acid
- S-cortisol. Always and regardless of time of day, but preferably obtain a morning value at 8.00, where <140 nmol/L indicates adrenal insufficiency, 140-275 nmol/L – suspiciously low value – while values of >400 nmol/L speak against cortisol deficiency.
- P-ACTH. Always taken regardless of time of day but preferably obtain a morning value, where elevated levels support the diagnosis of Mb Addison.
- Circulating antibodies against 21-hydroxylase in the adrenal cortex.
- Continue to monitor Na, K, Ca and Creatinine, depending on the patient’s general condition and fluid needs, for example, 2 times per day for the first day.
- Fast Synacthen ( tetracosactide ) test with 250μg test substance (see below):
Normal response (S-cortisol> 500 nmol/L after 30 or 60 minutes, note – assay dependent) rules out primary adrenal cortex defect.
Note – Poor response to rapid Synacthen test does not have to mean that the patient has Mb Addison. Consider any underlying pituitary insufficiency or prolonged steroid use with subsequent atrophy of the adrenal glands.
- The value of the long Synacthen test (see below) can be debated but is no longer recommended.
- CT of the adrenal glands (needs not be done if there is a high suspicion of autoimmune etiology).
- The use of saliva-cortisol in the diagnosis of adrenal insufficiency is gaining ground, but the method is not yet used in all hospital laboratories.
Treatment – Addison’s disease
- Hydrocortisone (Solu-Cortef) 100 mg iv + 100 mg im, then 100 mg im or iv every 4 hours, then lower doses in steps congruent with patient improvement.
- Plenty of iv fluids. Up to 5 liters of NaCl/glucose in the first 24 hours.
- Follow heart rate, blood pressure and electrolytes.
- Note – It is important to begin treatment in case of clinical suspicion, even if the diagnosis has not been confirmed in the laboratory.
- The above treatment can also be applied to patients with already known Addison diagnosis, who have become ill with, for example, gastroenteritis or other acute ailments, eg fever over 39 degrees, which is a life-threatening condition for patients with Mb Addison. Those patient groups should then seek emergency care. This also applies to patients with secondary adrenal cortex failure with an acute condition.
Maintenance treatment should be individually tailored. The current recommendation is to try to give lower doses of hydrocortisone, compared to before. Most patients respond well to 15-25 (-30) mg daily, preferably divided into three doses per day.
Plenadren is approved within the EU for the treatment of adrenal insufficiency. This is a new form of hydrocortisone with both a rapid and a delayed-release, enabling once-daily dosing, as well as a more physiological plasma profile of cortisol, compared to conventional hydrocortisone treatment. The studies available confirm some of the metabolic benefits of this form of preparation.
Most patients need supplementation of mineral corticoid fludrocortisone, Florinef 0.1 mg 0.5-1 x 1.
Treatment with dehydroepiandrosterone (DHEA) in women with adrenal insufficiency may be considered, but the literature is far from conclusive. Some studies have shown beneficial effects regarding increased quality of life, while others have not been able to confirm this. Dermatological side effects mainly in the form of oily skin and acne are common.
Keep in mind that patients with adrenal insufficiency need extra substitution in the event of any surgical intervention. There are no absolute rules of thumb for how to do this, but an example of such treatment may be 100 mg of hydrocortisone (Solu-Cortef) iv before surgery and then another 100 mg iv x 2-3 during the remainder of the day of surgery.
The day after a surgical procedure, an additional 100 mg of Solu-Cortef iv x 2-4 can be given depending on the extent, duration and general condition of the patient. The following day, the aim is to allow the patient to return to normal po substitution, but if you are unsure, you can continue with Solu-Cortef iv tapering dose, eg 50 mg x 4, or 50 mg x 2.
Febrile patients should be instructed to increase the dose by 20 mg of hydrocortisone in tablet form per temperature degree increase over 37 degrees.
Give thorough oral and written information to the patient. The patient should be equipped with a “cortisone card” which indicates the patient’s diagnosis and need for cortisone substitution in other acute illness!
Short Synacthen Test (SST)
Tetracosactide (Synacthen) is a synthetically produced polypeptide analog to ACTH. Side effects are rare but allergic reactions may occur.
S-cortisol is taken immediately before and 30 minutes after injection of 0.25 mg (1 ml) of tetracosactide iv
Long Synachten Test (LST)
Extends over 3 days with iv infusion on the 1st day and im injections days 2 and 3, as follows:
- Day 1: Morning test of S-cortisol – start collecting U-cortisol. Infusion 800 mL 0.9% NaCl + 0.75 mg (= 3 mL = 3 ampoules) Synacthen iv which runs for 8 hours. S-cortisol after 4, 6 and 8 hours of infusion.
- Day 2,3: S-cortisol at 8:00, followed by tetracosactide (Synacthen Depot) 1 mg im – New S-cortisol at 16:00. Urine collection for the determination of U-cortisol.
Failure to elevate S-cortisol and U-cortisol levels following the long Synachthen test assay confirms the diagnosis of primary adrenal cortex insufficiency.
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- CTLA-4 as a genetic determinant in autoimmune Addison’s disease
- A Systematic Review and Meta-Analysis of Endocrine-Related Adverse Events Associated with Immune Checkpoint Inhibitors