Addison's Disease: Rare Autoimmune Disorder with Late Diagnosis Challenges

Addison’s disease (AD) is characterized by primary adrenocortical insufficiency. Most of the cases originally described were caused by tuberculosis (TB), but currently, in the United Kingdom, the most common etiology is autoimmunity .

AD remains rare; Its prevalence is approximately 120/million inhabitants. Delay in diagnosis is common due to lack of recognition resulting from the insidious onset of symptoms . A survey revealed that 60% of AD patients had sought medical care from 2 or more physicians before the diagnosis was considered.

Anatomy and pathophysiology

The adrenal glands are Y-shaped (each limb measures <5 mm) and are located at the upper poles of the kidneys. They comprise a cortex (90%) that surrounds the medullary part (10%).

The bark secretes:

• Cortisol , a glucocorticoid from the zona fasciculata.
   
• Androgens (e.g., dehydroepiandrosterone (DHEA) from the zona reticularis.
   
• Mineralocorticoids (aldosterone) of the zona glomerularis, predominantly under the control of the reninangiotensin system (although 5-10% of total aldosterone production is mediated by adrenocorticotrophic hormone [ACTH]).

AD involves all three areas of the adrenal cortex.

Symptoms usually do not appear until more than 90% of the gland is destroyed.

Concentrations of glucocorticoids, mineralocorticoids, and androgens are reduced, in contrast to the situation in secondary adrenal insufficiency (ACTH deficiency), in which mineralocorticoid secretion remains relatively preserved. Immune destruction leads to fibrosis, with an infiltrate of mononuclear cells, sometimes plasma cells and, rarely, germinal centers.

Etiology

In developed countries, 75 to 80% of AD cases are caused by autoimmune destruction . It is next in frequency to TBC since the other causes are even rarer. In young patients, the most likely cause is autoimmunity, with a higher risk of developing autoimmune AD if the individual was born in winter.

Patients with autoimmune AD have a 50 to 60% risk of developing another autoimmune disorder (10% of patients develop type 1 diabetes mellitus). There is an association with human leukocyte antigen (HLA)-DR3 and HLA-DR4. Although adrenal metastases are relatively common, hormonal insufficiency is unusual.

Clinical features

Patients may present with an insidious onset of nonspecific symptoms, or during an adrenal crisis, depending on the acuity of the hormonal deficit and any intercurrent illness. Primary adrenal insufficiency is suspected when hyperpigmentation is found (as a consequence of elevated melanocyte-stimulating hormone and ACTH) in the oral mucosa, nail bed, and areas exposed to light and pressure.

Investigations and diagnosis

Biochemical abnormalities

Initially, patients usually present with hyponatremia, hyperkalemia, and acidosis.

Mineralocorticoid deficiency leads to sodium depletion, reduced extracellular fluid volume, and hypotension, resulting in elevated plasma renin concentration. This can precede cortisol deficiency by several years.

Reduced renal water clearance leads to hyponatremia . Hyperkalemia develops as a result of reduced renal excretion of potassium and hydrogen ions, leading to type IV renal tubular acidosis .

Low plasma glucose (due to reduced glycogen stores) is common, although in adults, severe hypoglycemia is rare .

Reversible hypercalcemia may occur .

The diagnosis can be ruled out if there is low clinical suspicion and a serum cortisol at 09:00 hours >300-500 nmol/l (10.87 µg/dl) (depending on the assay). At 9:00 a.m., serum cortisol <100 nmol/l (14.5 µg/dl) with elevated ACTH is usually diagnostic of deficiency.

Cortisol secretion maintains a circadian rhythm (higher upon awakening) that is increased in the ill (e.g., sepsis), which must be considered when interpreting any random measurement of serum cortisol.

Patients taking oral contraceptives or an exogenous corticosteroid should discontinue them before testing, whenever safe, as results may be misleading.

Tetracosactide test

The diagnosis is confirmed by a suboptimal cortisol response to synthetic ACTH in patients with high clinical suspicion or low values ​​on a 9:00 a.m. cortisol detection test.

Administration of tetracosactide , 250 mcgr intramuscularly (im) or intravenously (iv) is administered at 09:00 hours, and serum cortisol will be measured at 0.30 (or 60) minutes. In practice, the most frequently used response for diagnosis is the 30-minute response, as it has been validated against insulin tolerance, which is the gold standard test.

However, the 60-minute serum cortisol concentration may be more specific for adrenal insufficiency. All 3 values ​​are usually not necessary. Sometimes false negative results are obtained.

Tetracosactide deposition can also be used to distinguish secondary adrenal insufficiency; 1 mg im is administered and serum cortisol is measured at 0, 6, and 24 hours. In AD there is no increase after 6 hours, which does occur in secondary adrenal insufficiency.

Investigations to establish the etiology

Once primary adrenal insufficiency has been diagnosed, the cause must be established.

Antibodies against enzymes in the adrenal cortex (e.g., 21-hydroxylase, P450scc, 17-hydroxylase) appear in more than 90% of patients with adrenal autoimmunity, although only 20% of people detect autoimmunity. with positive antibodies they develop AD.

If there is clinical suspicion of TB, chest and abdominal x-rays will be requested to look for apical shadows and adrenal calcification.

Computed tomography ( CT) of the adrenal glands will be requested only when metastasis, infiltrative process or TB are suspected.

Adrenal insufficiency may be associated with a moderate and reversible elevation of serum thyroid-stimulating hormone.

Treatment

Treatment aims to replace deficient hormones and treat any reversible causes of adrenal disease. Up to 30% of AD patients have detectable but low cortisol, increasing the possibility of regenerating adrenal tissue through novel treatments.

Glucocorticoids

Generally, glucocorticoid replacement is done by administering hydrocortisone, 3 times/day (total 15-25 mg) . The highest dose is taken before getting out of bed, to mimic the physiological peak just before waking up; additional doses are taken at 12:00 and 18:00.

In healthy people, cortisol production rates vary considerably and the goal should be to provide the minimum dose to avoid insufficiency and maintain the well-being of the individual. Alternatively, 3-5 mg of prednisolone is sometimes used, particularly when compliance with multiple doses is a problem.

An alternative is a double-release hydrocortisone preparation taken once/day, which reduces overall exposure to cortisol, improving glycemic control in 10% of patients with coexisting type 1 diabetes mellitus; It can also improve adherence but there is not enough evidence to recommend it routinely.

Likewise, continuous subcutaneous infusions have been used (in trials); that allow the pulsatility of cortisol, very important at a transcriptional level.

Mineralocorticoids

Fludrocortisone treatment aims to achieve normal levels of sodium homeostasis, such as normal plasma or slightly elevated renin activity. An initial dose of 0.1 mg/day is adequate for most patients, but doses up to 0.1 mg twice/day may be necessary.

Monitoring is usually done through clinical evaluation and measurement of electrolytes. Overtreatment may cause hypertension and, rarely, edema; It is detected clinically or by suppression of plasma renin activity.

Adrenal androgens

Compared to the general population, people with AD have a reduced quality of life, with fatigue being one of its symptoms.

DHEA replacement can improve self-esteem and mood; In some patients it may also improve fatigue and libido, which may be boosted by testosterone. A trial of 25 to 50 mg of DHEA is helpful in some women, but meta-analyses have not found an overall benefit.

Management during intercurrent illnesses

Endogenous adrenocortical secretion increases in critically ill patients and in the perioperative period of patients with healthy adrenal glands. In people with adrenal insufficiency, glucocorticoid doses should be doubled during significant febrile illnesses to mimic the normal physiologic response.

Patients should keep a vial of hydrocortisone in their refrigerator, for IM injection in case of severe illness, trauma, vomiting or diarrhea

100 mg of hydrocortisone IV or imy saline IV should be administered to avoid adrenal crisis. This should be continued every 6 hours or as a continuous infusion while the patient is in seizure.

Although there is no formal definition of crisis, it is generally accepted as an acute deterioration in health associated with hypotension that resolves within 1-2 hours of parenteral administration of glucocorticoids.

It is not necessary to replace mineralocorticoids if high doses of hydrocortisone are used, which has a significant mineralocorticoid effect, as a result of saturation of renal 11ß-hydroxysteroid dehydrogenase type 2 activity.

Patient education

Each patient should receive a steroid emergency card, which outlines initial treatment for patients at risk for adrenal insufficiency and crisis. This should be provided as part of a treatment plan that includes education about corticosteroid escalation in severe intercurrent illness, often called " sick day rules ." In addition to receiving written information (including about support groups), patients must register an alert with the ambulance service and alert systems.

AD has been associated with a 2-fold increase in the standardized mortality rate, mainly related to cardiovascular, malignant and infectious diseases.

Patients with AD have a 6%-8% risk of adrenal crisis each year, but this has large individual variations. A key objective should always be the optimization of replacement therapy, to mimic normal physiology as much as possible.