Inflammation of the adrenal glands, called adrenalitis, damages these small hormone-producing organs that sit on top of the kidneys and can lead to a shortage of cortisol and other critical hormones. The most common trigger in wealthy countries is an autoimmune attack, while tuberculosis remains the leading cause in much of the developing world. Because the adrenal glands regulate stress responses, blood pressure, and electrolyte balance, even partial destruction can produce wide-ranging symptoms, from relentless fatigue and low blood pressure to dangerous electrolyte imbalances and, in severe cases, life-threatening shock.
Why the Immune System Turns on the Adrenal Glands
Autoimmune adrenalitis, the process behind what is traditionally called Addison’s disease, accounts for the majority of primary adrenal insufficiency cases in Europe, North America, and other industrialized regions. The immune system mistakenly targets an enzyme called 21-hydroxylase that the adrenal cortex needs to make cortisol and aldosterone. Autoantibodies against this enzyme are found in over 90 percent of patients with autoimmune Addison’s disease, though researchers believe the antibodies themselves are not the direct cause of tissue destruction.1PubMed Central. High frequency of cytolytic 21-hydroxylase-specific CD8+ T cells in autoimmune Addison’s disease patients Instead, immune cells called cytotoxic T cells appear to be the ones that physically infiltrate the adrenal cortex and kill its hormone-producing cells.
The presence of 21-hydroxylase autoantibodies is a reliable marker for diagnosing the autoimmune form, and they are linked to specific genetic risk profiles. However, some patients with long-standing disease eventually test negative for these antibodies, so a negative result does not rule out an autoimmune origin.2PubMed Central. The natural history of 21-hydroxylase autoantibodies in autoimmune Addison’s disease This slow fade in antibody levels can confuse diagnosis if a blood test is only done years after symptoms first appeared.
Autoimmune adrenalitis rarely happens in isolation. It often clusters with other autoimmune conditions in what clinicians call autoimmune polyendocrine syndromes. One form is linked to mutations in a single gene called AIRE that governs immune tolerance; the other is tied to specific immune-system gene variants and tends to pair Addison’s disease with autoimmune thyroid disease or type 1 diabetes. There is considerable overlap in symptoms and circulating antibodies between the two patterns, which can make classification tricky in practice.
Infections That Can Destroy the Adrenal Glands
Before autoimmune disease was widely recognized, tuberculosis was the textbook cause of adrenal failure. Thomas Addison’s original case descriptions in the 1850s involved patients whose adrenal glands had been wrecked by TB. In much of the developing world, TB remains the most common reason for primary adrenal insufficiency.3PubMed Central. Current Approach for Diagnosis and Treatment of Adrenal Tuberculosis-Our Experience and Review of Literature The bacterium reaches the adrenals through the bloodstream, and the resulting granulomatous inflammation with tissue death can enlarge the glands early on, then shrink and calcify them over time. Biopsy of affected tissue typically shows chronic inflammation with characteristic giant cells and areas of necrosis consistent with a granulomatous process.4PubMed Central. Primary Adrenal Insufficiency Due to Tuberculous Adrenalitis in a Patient without Active Pulmonary Tuberculosis Importantly, adrenal TB can develop even without active lung disease, which sometimes delays diagnosis for months.5PubMed Central. Addison’s Disease Caused by Tuberculosis: Diagnostic and Therapeutic Difficulties
Cytomegalovirus (CMV) is another infectious culprit, though it overwhelmingly affects people whose immune systems are compromised. In patients with AIDS, CMV can disseminate through the bloodstream to many organs, and the adrenal glands appear to have a particular affinity for the virus. Acute adrenalitis triggered by CMV has been described as the first clinical presentation in a substantial proportion of these cases, sometimes causing severe drops in blood pressure and risk of shock.6Hematology, Transfusion and Cell Therapy. Acute lymphoblastic leukemia complicating with adrenal insufficiency due cytomegalovirus infection CMV-induced adrenal insufficiency has also been reported in people immunosuppressed by chemotherapy and, rarely, in infants without HIV.7PubMed. Adrenal insufficiency associated with cytomegalovirus infection in two infants One case involved a man treated for lymphoma who developed adrenal failure after several rounds of chemotherapy weakened his immune defenses enough for CMV to take hold.8PubMed Central. Primary Adrenal Insufficiency Triggered by Cytomegalovirus Infection after Obinutuzumab Plus Bendamustine Therapy for Follicular Lymphoma
Fungal infections can do the same kind of damage. Histoplasmosis, caused by a soil-dwelling fungus common in certain river valleys and tropical regions, spreads through the body’s immune cell network and can reach the adrenal glands, triggering granulomatous inflammation and outright gland destruction.9PubMed Central. Histoplasmosis: An Unusual Cause of Adrenal Insufficiency In rare instances this occurs in people with otherwise healthy immune systems, with the adrenal glands being the only detectable site of infection.10PubMed Central. Bilateral adrenal histoplasmosis presenting as adrenal insufficiency in an immunocompetent host in the Philippines
Drug-Induced Adrenalitis
A newer and increasingly recognized cause of adrenal gland inflammation is immune checkpoint inhibitor therapy, a class of cancer drugs that release the brakes on the immune system so it can attack tumors more aggressively. The downside is that an unleashed immune system can also attack healthy tissue, including the adrenal cortex. Primary adrenal insufficiency occurs in roughly one to two percent of patients receiving a single checkpoint inhibitor drug and in a higher range of about four to nine percent when two checkpoint drugs are combined.11PubMed. Primary adrenal insufficiency induced by immune checkpoint inhibitors: biological, clinical, and radiological aspects
Although the overall percentage sounds small, the absolute number of affected people is growing rapidly because checkpoint inhibitors are now used to treat a wide and expanding list of cancers. The adrenalitis these drugs cause can be directly visible on imaging scans as enlarged, inflamed glands.12Endocrinology and Metabolism. Immune Checkpoint Inhibitors and Endocrine Disorders: A Position Statement from the Korean Endocrine Society It tends to present acutely and can be life-threatening if missed, making routine monitoring of cortisol levels an important part of cancer care for these patients.13PubMed. Immune Checkpoint Inhibitor-Induced Adrenalitis and Primary Adrenal Insufficiency: Systematic Review and Optimal Management
Waterhouse-Friderichsen Syndrome and Adrenal Hemorrhage
Not all adrenal destruction comes from a slow inflammatory process. In Waterhouse-Friderichsen syndrome, overwhelming bloodstream infection causes massive bleeding into both adrenal glands, essentially destroying them in hours. The syndrome is classically associated with meningococcal sepsis, but it can be caused by other bacteria as well.14PubMed Central. Waterhouse-Friderichsen syndrome as a result of non-meningococcal infection Cases have been documented in children with Staphylococcus aureus infections, where bilateral adrenal hemorrhage was found at autopsy.15PubMed. Staphylococcus aureus sepsis and the Waterhouse-Friderichsen syndrome in children This is among the most dramatic and rapidly fatal forms of adrenal failure, and it often presents with a distinctive skin rash called purpura fulminans alongside plummeting blood pressure.16PubMed. Rupert Waterhouse and Carl Friderichsen: adrenal apoplexy
Symptoms That Build Slowly
When inflammation erodes the adrenal glands gradually, as it does in autoimmune or tuberculous adrenalitis, symptoms tend to creep in over weeks to months. The presenting complaints are frustratingly vague: persistent tiredness, loss of appetite, unintentional weight loss, and a general sense of being unwell. Because these symptoms overlap with dozens of other conditions, diagnosis is often delayed.17The Lancet. Adrenal insufficiency
More specific clues do emerge as cortisol and aldosterone levels drop further. Hallmark features of primary adrenal insufficiency include darkening of the skin (especially in skin creases, gums, and scars), craving for salty foods, low blood pressure that worsens when you stand up, and an imbalance in blood electrolytes with sodium falling and potassium rising.18PubMed. Endocrine disorders: causes of hyponatremia not to neglect The skin darkening happens because the pituitary gland ramps up production of the hormone ACTH in a desperate attempt to stimulate the failing adrenals, and ACTH shares a chemical precursor with a pigment-stimulating hormone.19PubMed Central. Addison’s disease presenting with hyperpigmentation This is one of the most recognizable signs, but it only appears in primary adrenal failure, not when the problem originates in the pituitary gland.
Nausea, vomiting, abdominal pain, and muscle or joint aches round out the chronic symptom picture. Some people develop mood changes, difficulty concentrating, or low blood sugar. In women, loss of body hair (especially underarm and pubic hair) can occur because the adrenal glands are the main source of certain androgens in the female body.
When It Becomes a Crisis
The danger of adrenal inflammation is not just chronic hormone deficiency; it is the potential for acute collapse. An adrenal crisis can develop when someone with compromised adrenal function encounters a physical stress the body cannot meet with its limited cortisol supply. Common triggers include infections, surgery, emotional distress, or abruptly stopping corticosteroid medications.20PubMed. Diagnosis and management of secondary adrenal crisis
During a crisis, blood pressure can plummet, sodium drops to dangerously low levels, and mental status may deteriorate from confusion to unconsciousness. Without emergency treatment, adrenal crisis can be fatal. This is why every person diagnosed with adrenal insufficiency should carry an emergency injection of hydrocortisone and know how to increase their daily dose during illness, a practice called “sick day rules.”21JAMA. Adrenal Insufficiency in Adults: A Review A new presentation of adrenal insufficiency can range from nonspecific fatigue all the way to hemodynamic instability with shock, making it easy to miss in emergency departments when no prior diagnosis exists.22PubMed. Diagnosis and Management of Adrenal Insufficiency and Adrenal Crisis in the Emergency Department
How the Cause Is Identified
Establishing that adrenal insufficiency exists is only the first step. The harder part is figuring out why the glands are inflamed or damaged, because treatment depends on the underlying cause. A morning cortisol blood test, sometimes followed by a stimulation test, confirms that the adrenals are underperforming. Measuring ACTH helps distinguish primary adrenal failure (where ACTH is high, because the pituitary is trying to compensate) from secondary failure (where ACTH is low, because the pituitary is the problem).23Clinical Medicine. Diagnosis and management of adrenal insufficiency
Once primary adrenal insufficiency is confirmed, testing for 21-hydroxylase autoantibodies is the standard next move. A positive result points strongly to autoimmune adrenalitis. If the antibody test is negative, imaging becomes important. CT and MRI scans of the adrenal glands can reveal patterns that suggest specific causes: enlarged glands with areas of tissue death point toward active tuberculosis or fungal infection, while calcified, shrunken glands suggest a burned-out infection from years earlier.24PubMed Central. Evaluation of primary adrenal insufficiency secondary to tuberculous adrenalitis with computed tomography and magnetic resonance imaging: Current status Biopsy is occasionally needed when imaging is ambiguous, particularly to distinguish infection from cancer that has spread to the adrenal glands.
Rarer Inflammatory Causes
Beyond autoimmune disease, infections, and drug reactions, a few less common inflammatory conditions can also target the adrenal glands. IgG4-related disease is a chronic inflammatory disorder that produces dense infiltrations of immune cells and scarring in various organs. Almost forty different organ locations have been reported, and the adrenal glands are among them, though endocrine involvement overall is uncommon.25PubMed Central. IgG4-related disease in endocrine practice The condition typically causes organ enlargement and is associated with elevated IgG4 levels in the blood. Sarcoidosis can similarly produce granulomas in the adrenal glands, though clinically significant adrenal failure from sarcoidosis alone is rare. In both cases, corticosteroid treatment for the underlying inflammatory disease often also addresses the adrenal insufficiency, at least temporarily.
Who Gets Adrenal Inflammation
Primary adrenal insufficiency from any cause is uncommon. Estimated prevalence sits in the range of roughly one case per 5,000 to 7,000 people, with an incidence of about five to six new cases per million per year. Hospital admission rates for primary adrenal insufficiency average about 10 per million per year, with women admitted roughly twice as often as men.26PubMed Central. The Changing Epidemiology of Adrenal Insufficiency: Iatrogenic Factors Predominate Admission rates are highest among people aged 70 and older and have been declining in older men over recent decades, possibly reflecting changes in the underlying causes.
The geographic distribution of causes matters. If you live in a region where tuberculosis is common, infectious adrenalitis should be high on the list of suspects for anyone presenting with adrenal failure. In wealthier countries where TB has been largely controlled, autoimmune causes dominate. And in any oncology practice worldwide, checkpoint inhibitor-induced adrenalitis is an emerging concern that barely existed a decade ago.
Everyday Management of Damaged Adrenal Glands
Once adrenal inflammation has destroyed enough tissue to cause hormone deficiency, the damage is usually permanent. Treatment centers on replacing what the glands can no longer make. Standard glucocorticoid replacement involves hydrocortisone in the range of 15 to 25 milligrams daily, split into two or three doses to roughly mimic the body’s natural cortisol rhythm, or prednisone at 3 to 5 milligrams daily. People with primary adrenal insufficiency also need a mineralocorticoid, typically fludrocortisone at 0.05 to 0.3 milligrams daily, to maintain sodium-potassium balance and blood pressure.21JAMA. Adrenal Insufficiency in Adults: A Review
Getting the dose right is part science and part art. Too little replacement leaves you tired, nauseated, and at risk of crisis. Too much over months and years can contribute to weight gain, bone thinning, and metabolic problems. Doctors adjust doses based on symptoms, blood pressure, and electrolyte levels rather than relying on a single cortisol number, because replacement hormones do not perfectly replicate the body’s pulsatile secretion pattern.
Beyond the daily pill regimen, the most important practical skill is knowing how to handle stress doses. Any significant illness, injury, or surgery requires temporarily doubling or tripling the glucocorticoid dose to cover the body’s increased cortisol demand. For situations where you cannot keep pills down, such as vomiting from a stomach bug, an intramuscular injection of 100 milligrams of hydrocortisone can be lifesaving. Patients are advised to carry an emergency kit with this injection, along with a medical alert bracelet or card, at all times.
Adrenal Inflammation in Children
Adrenal insufficiency looks a bit different in younger patients. In infants and toddlers, the autoimmune form may appear as part of a rare genetic syndrome caused by mutations in the AIRE gene, which normally teaches the immune system not to attack the body’s own tissues. Children with this condition often develop adrenal failure alongside other autoimmune problems such as chronic yeast infections of the mouth and skin, and underactive parathyroid glands. The combination tends to appear in childhood, sometimes before age ten, while the more common non-genetic autoimmune polyendocrine syndrome typically surfaces in adults.
Recognizing adrenal insufficiency in children is tricky because the early signs, such as poor appetite, low energy, and vague abdominal complaints, overlap with routine childhood illnesses. Unexplained low blood sugar in a child, or darkening of the skin without obvious sun exposure, should prompt testing. Infections like CMV can also cause adrenal damage in infants, though this is rare outside the context of immune compromise.7PubMed. Adrenal insufficiency associated with cytomegalovirus infection in two infants Growth monitoring and careful dose adjustment are essential in pediatric patients, since both undertreated adrenal insufficiency and excessive glucocorticoid replacement can interfere with normal development.