Profound fatigue that never seems to lift, unexplained weight loss, muscle weakness, and a strange darkening of the skin—these are just some of the vague but debilitating symptoms that can slowly and insidiously develop over months or even years. For those experiencing them, the journey to a diagnosis can be long and frustrating. These symptoms can be the hallmark of Addison’s disease, a rare but serious disorder where the adrenal glands fail to produce enough of two essential hormones. If left undiagnosed and untreated, Addison’s disease can be life-threatening. However, with a proper diagnosis and lifelong hormone replacement therapy, individuals with this condition can manage their health effectively and lead full, active lives.

Addison’s disease, also known as primary adrenal insufficiency, is a rare, chronic condition in which the adrenal glands don’t produce enough of certain hormones, particularly cortisol and aldosterone. To understand the disease, it is crucial to understand the vital role these small glands play.

The body has two adrenal glands, each situated on top of a kidney. Despite their small size, they are powerful hormone factories. The outer layer of the gland, the adrenal cortex, produces two critical hormones:

1. Cortisol: Often called the body’s main “stress hormone,” cortisol is essential for life. It plays a central role in nearly every organ and tissue. Its many jobs include maintaining blood pressure, regulating blood sugar levels, controlling the body’s use of fats, proteins, and carbohydrates, and suppressing inflammation. In times of physical stress, like an infection, injury, or surgery, the body dramatically increases its cortisol output to help you cope.
2. Aldosterone: This hormone is part of a system that regulates the balance of sodium and potassium in your blood. By managing salt and water levels, aldosterone plays a direct role in controlling your blood volume and blood pressure.

Without these hormones, the body cannot manage stress, maintain adequate blood pressure, or keep its electrolytes in balance, leading to the wide range of symptoms that define the condition.

Analogy: Think of cortisol and aldosterone as thermostats regulating energy and fluid in your body. Addison’s disease is like having a broken thermostat, you can’t maintain balance, leading to overheating (stress intolerance) or freezing (low energy and blood pressure).

Addison’s disease happens when the adrenal glands are damaged, preventing them from producing enough hormones. This destruction can happen for several reasons, but the causes vary significantly in different parts of the world.

Autoimmune Adrenalitis: In Western countries, the most common cause of Addison’s disease, accounting for about 80% of cases, is an autoimmune disorder. In this condition, the body’s own immune system, which is supposed to fight off infections, mistakenly identifies the adrenal cortex as a foreign invader and produces antibodies that attack and destroy it. Why the immune system does this is not fully understood, but it often occurs in people who have other autoimmune conditions.

Infections: Globally, infections are a major cause of adrenal gland destruction.

• Tuberculosis (TB): Historically, and still in many parts of the world where TB is endemic, tuberculosis is a leading cause of Addison’s disease. The bacteria can infect the adrenal glands and destroy them over time.
• Other Infections: Severe fungal infections and cytomegalovirus (CMV), particularly in people with weakened immune systems (such as those with HIV/AIDS), can also damage the adrenal glands.

Other Rare Causes: Less common causes of adrenal gland failure include:

• Bleeding into the adrenal glands (adrenal hemorrhage): This can be a complication of certain blood-thinning medications or severe bloodstream infections (sepsis).
• Cancer: Cancer that has spread (metastasized) from other parts of the body, like the lungs or breast, to the adrenal glands.
• Surgical Removal: The surgical removal of both adrenal glands.
• Genetic Defects: Certain rare genetic disorders can affect the development or function of the adrenal glands.

You “get” Addison’s disease when damage to the adrenal glands leads to hormone deficiency. This damage is usually gradual, and symptoms may not appear until more than 90% of the adrenal cortex is destroyed.

You may be at a higher risk for developing Addison’s disease if you:

• Have another autoimmune condition: People with Addison’s disease often have other autoimmune disorders, such as Type 1 diabetes, pernicious anemia (a vitamin B12 deficiency), vitiligo (a condition causing patches of light skin), or autoimmune thyroid disease (Hashimoto’s thyroiditis or Graves’ disease). When these conditions occur together, it is sometimes called an autoimmune polyglandular syndrome.
• Have a family history of Addison’s disease: While most cases are not directly inherited, having a close relative with the condition can slightly increase your risk, suggesting a genetic predisposition to autoimmunity.
• Have had chronic infections like tuberculosis.
• Have had cancer that is known to spread to the adrenal glands.

Patients often assume the symptoms come from burnout or fatigue, but Addison’s has a distinct biochemical fingerprint, it’s not about willpower; it’s about hormone deficiency.

Addison’s disease symptoms develop gradually, and may go unnoticed or be mistaken for stress, depression, or chronic fatigue. When symptoms worsen suddenly, it can lead to an Addisonian crisis, a medical emergency.

The most common signs and symptoms, which tend to worsen over time, include:

• Chronic, debilitating fatigue and muscle weakness.
• Unintended weight loss and reduced appetite.
• Hyperpigmentation: This is one of the most classic and specific signs of Addison’s disease. It is a darkening of the skin that may look like a suntan, but it also appears on areas not exposed to the sun. This is caused by the pituitary gland producing an excess of ACTH to try to stimulate the failing adrenal glands; a byproduct of this process also stimulates the skin’s melanin-producing cells. The darkening is often most noticeable in skin creases (like on the palms), on scars, on pressure points (like elbows and knees), and on the gums.
• Low blood pressure (hypotension): This can cause dizziness or lightheadedness, especially when standing up from a sitting or lying position.
• Salt craving: An intense craving for salty foods is common, caused by the body losing sodium due to the lack of aldosterone.
• Gastrointestinal issues: Nausea, vomiting, diarrhea or abdominal pain.
• Muscle and joint pain
• Psychological symptoms: Irritability, depression, and poor concentration.
• Low blood sugar (hypoglycemia).

Because the early symptoms are so non-specific, a doctor often first suspects Addison’s disease based on the presence of hyperpigmentation or unexplained low blood pressure. A definitive diagnosis involves blood tests and stimulation testing to measure hormone levels.

1. Initial Blood Tests: A basic blood panel may provide the first clues. The results often show low levels of sodium, low levels of glucose, and high levels of potassium. A baseline morning blood test may also show a very low level of cortisol.
2. ACTH Stimulation Test: This is the gold standard test for diagnosing Addison’s disease.
   • The test involves measuring a patient’s blood cortisol level.
   • Then, the patient is given an intravenous (IV) injection of a synthetic form of ACTH (the hormone that tells the adrenal glands to work).
   • Blood is drawn again after 30 to 60 minutes to re-measure the cortisol level.
   • Normal response: A healthy person’s adrenal glands will respond to the ACTH signal by producing a large surge of cortisol.
   • Addison’s disease response: In a person with Addison’s, the damaged adrenal glands are unable to respond to the ACTH signal, and the cortisol level remains low. This confirms the diagnosis of primary adrenal insufficiency.
3. Determining the Cause: Once Addison’s is confirmed, further tests are done to find the underlying cause. This may include a blood test for adrenal autoantibodies to confirm an autoimmune cause or a CT scan of the abdomen to look for signs of infection, bleeding, or tumors in the adrenal glands.

Clinically, the ACTH stimulation test is the gold standard and most definitive test. If the adrenals fail to produce cortisol after stimulation, the diagnosis is confirmed.

There is no cure for Addison’s disease, but lifelong hormone replacement therapy can manage it effectively.

Hormone Replacement Therapy

• Replacing Cortisol: This is done with oral glucocorticoid drugs. Hydrocortisone is most used because it is identical to the body’s natural cortisol. It is typically taken in two or three divided doses throughout the day to mimic the body’s natural cortisol rhythm.
• Replacing Aldosterone: This is done with an oral mineralocorticoid medication called fludrocortisone, usually taken once a day. This helps normalize the body’s sodium and potassium levels, which in turn stabilizes blood pressure.

Preventing an Adrenal Crisis: The “Sick Day Rules”

This is the most critical aspect of living safely with Addison’s disease. Because the body cannot produce extra cortisol on its own, patients must learn to increase their steroid dose during times of physical stress.

• Stress Dosing: During a minor illness with a fever, such as the flu, the oral hydrocortisone dose should be doubled or tripled for a few days until the illness resolves.
• Emergency Injection: If a person with Addison’s is experiencing severe vomiting or diarrhea and cannot keep their oral medication down, or if they suffer a major injury, they need an emergency intramuscular injection of hydrocortisone.
• Emergency Kit and Medical ID: Every person with Addison’s disease must have an emergency kit containing injectable hydrocortisone and be trained (along with their family) on how to administer it. They should also wear a medical alert bracelet or necklace at all times to inform emergency responders of their condition.

With proper medication and awareness, patients with Addison’s can live full, active lives.

Addison’s disease is a rare and serious condition resulting from adrenal gland failure. Its slow and subtle onset can make it difficult to diagnose, but its characteristic signs, like skin hyperpigmentation and low blood pressure, can provide crucial clues. While the prospect of a lifelong condition can be intimidating, the reality of living with Addison’s disease in the modern era is one of effective management and control. Through diligent daily hormone replacement therapy and, most importantly, a clear understanding of how to increase steroid doses during times of illness or stress, individuals with Addison’s disease can prevent a life-threatening adrenal crisis.

• National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). (2018). Adrenal Insufficiency & Addison’s Disease. Retrieved from https://www.niddk.nih.gov/health-information/endocrine-diseases/adrenal-insufficiency-addisons-disease
• Mayo Clinic. (2023). Addison’s disease. Retrieved from https://www.mayoclinic.org/diseases-conditions/addisons-disease/symptoms-causes/syc-20350293
• Arlt, W., & Allolio, B. (2003). Adrenal insufficiency. Lancet, 361(9372), 1881–1893. https://doi.org/10.1016/S0140-6736(03)13492-7