Addison’s Disease: Symptoms, Causes, Risks, Diagnosis, Treatment and Outlook

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addison's disease

1Overview

Addison’s disease is a disease of the endocrine, or hormonal, system. It is also called primary adrenal insufficiency and affects the production of mineralocorticoids and glucocorticoids by the adrenal glands. In the developed world, Addison’s disease affects 39-144 per million people. However, it is a relatively rare disease, with a prevalence of about 140 per million.

If left untreated, Addison’s disease is potentially fatal. Yet, its diagnosis is often delayed or even missed. Furthermore, studies have shown that patients with Addison’s disease have a perception of poorer quality of life and they also remain at risk for early mortality.

The disease is characterized by orthostatic hypotension, fever, abdominal pain, agitation, circulatory collapse, and agitation. Acute adrenal decompensation is due to hemorrhage itself or by cancers of the adrenal gland, which are often precipitated by infections.

2Symptoms

The clinical manifestations of Addison’s disease are due to the lack of all adrenocortical hormones (cortisol, aldosterone, and androgens). They can also include signs and symptoms of other autoimmune conditions. Most of the symptoms of Addison’s disease are nonspecific and this is the reason why diagnosis is usually delayed.

In children, hypoglycemia is often a first presenting sign and it can lead to the decline of glycemic control, as well as the need for a reduction in total daily insulin dose for patients with type I diabetes.

Hyperpigmentation is a specific sign of chronic primary adrenal insufficiency.
This affects the areas of the skin where the pressure is greatest, such as the knuckles, palm creases, elbows, buccal mucosa, and lips. It is the caused by the over-stimulation of the melanocortin-1 receptor because of the high concentrations of circulating corticotropins. In darker-skinned people, hyperpigmentation is harder to recognize. Extensive and progressive hyperpigmentation of the areas that were stated should alert doctors to a possible diagnosis of Addison’s disease. However, increasing the color or pigmentation of the skin is not diagnostic of Addison’s disease. Scalp hair may also become darker and new moles can be observed. The ear cartilage may also calcify and harden.

Other symptoms include anorexia, accompanied by weight loss. In children, this can manifest as failure to grow or thrive. Fatigue, lack of energy, and reduced strength are also characteristic of the disease. Joint and muscle pain (myalgia) are other symptoms, along with salt cravings. Dry and itchy skin, specifically in women, is another sign.
Another sign specific to women is the loss or impairment of the libido.

Fever is a symptom caused by glucocorticoid deficiency. Postural hypotension and dehydration are pronounced in primary adrenal insufficiency. Loss of pubic hair or axillary hair may occur in women. 

3Causes

 The causes of Addison’s disease include autoimmune adrenalitis, which may or may not be part of a larger syndrome affecting the endocrine system. Autoimmune Addison’s disease is marked by the cell-mediated immune mechanisms that destroy the adrenal cortex.
In about 85% of patients, antibodies against steroid 21-hydroxylase are detected.
In healthy subjects, only 0.3% were positive for adrenal antibodies.

T cells and cellular immunity also have important roles in the cause of Addison’s disease. The production of antibodies can be due to tissue destruction. Furthermore, several genes confer the vulnerability to Addison’s disease. These include the MHC haplotypes DR3-DQ2 and DR4-DQ8.

Although Addison’s disease may be caused by infections, such as tuberculosis, most cases of Addison’s disease today are thought to be due to autoimmune disorders.
Autoimmune Addison’s disease may occur as a single condition or as part of a larger condition.

A wide variety of infections has been thought to cause Addison’s disease.
Of these infections, tuberculosis is the primary one. In most Western countries, tuberculosis accounts for only 15% of all cases of Addison’s disease.

Adrenal glands may also be sites of the metastasis of cancer from the lung, breast, kidney, and urinary bladder. Adrenal metastases can induce adrenal insufficiency, however, the prevalence of hypoadrenalism is poorly documented. In these cases, at least 90% of the adrenal gland should be replaced by tumors in order for hypoadrenalism to result. Thus, normal adrenal functions may persist even with significantly enlarged adrenal glands.

In children, the most common cause of Addison’s disease is congenital adrenal hyperplasia, which is a group of autosomal recessive disorders that results from the deficiency of one of the enzymes needed for the production of cortisol. The most common form is a 21-hydroxylase deficiency. This condition is marked by the low synthesis of glucocorticoids or even mineralocorticoids, in some cases. 

4Risk Factors

The risk factors for Addison’s disease include other autoimmune disorders. Swelling, or inflammation, of the thyroid gland, often leads to reduced thyroid function, which is termed as chronic thyroiditis. Overactive thyroid, wherein the gland produces too much thyroid hormone, is another risk factor. Dermatitis herpetiformis, which is characterized by itchy rashes with blisters and bumps, appears to be a risk factor for Addison’s disease.
Grave’s disease, an autoimmune disorder that leads to the hyperactivity of the thyroid gland, predisposes people to adrenal insufficiency. Hypoparathyroidism, wherein the parathyroid glands produce too little parathyroid hormones. Hypopituitarism may also cause Addison’s disease because it is a condition wherein the pituitary glands do not produce some or all of its hormones. Having autoimmune disorders that affect the nerves and the muscles they control can also lead to Addison’s disease. Having anemia, where the body does not have enough healthy red blood cells, is another risk factor, in addition to type I diabetes. Testicular failure, or the failure of the testicles to produce male hormones or sperm, makes a person vulnerable to Addison’s disease.

5Diagnosis

There are three main aims to diagnosing Addison’s disease, or any adrenal insufficiency. The first is to confirm that the cortisol secretion is inappropriately low. The second is to find out whether the adrenal insufficiency is central or primary, and the third aim is to find out the underlying pathological process.

Whatever the cause, diagnosing primary adrenal insufficiency depends on finding out the level of cortisol in the body. High cortisol-binding globulins in patients who are undergoing estrogen therapy or in pregnancy, however, can lead to false positive results.
Conversely, in patients with cirrhosis of the liver, cortisol-binding globulins are low, which can then lead to false abnormal results.

The measurement of serum free cortisol concentrations can offer added information.
In healthy people, serum cortisol levels are most increased in the early morning, when normal levels are 275-555 nmol/L. Thus, a low serum cortisol concentration taken during this time, with is defined as less than 80 nmol/L, strongly suggests Addison’s disease.

6Treatment

Addison’s disease is potentially life-threatening. As soon as the diagnosis is made, treatment should be initiated as soon as possible. Treatment should be started sooner if the patient is found to be in an adrenal crisis.

An important aspect of treatment is patient education and understanding that lifelong treatment is necessary. Replacement of glucocorticoids is recommended, and this should be increased when the patient is stressed. If the patient needs to undergo any surgical procedure, medical personnel should be informed right away of the patient’s condition.

Hydrocortisone injections should always be available for patients and they should be taught how to administer them. Patients with adrenal insufficiency should be treated using hydrocortisone, which is a replacement for glucocorticoids. The recommended daily dose of hydrocortisone is 10-12 mg/m2, which can be given in two or three divided doses.
In Addisons’ disease, mineralocorticoid therapy is needed to in order to prevent the loss of sodium. It can be given in the form of fludrocortisone, with doses of 0.05-0.20 mg every day.

In women, treatment with dehydroepiandrosterone may be necessary in order to improve mood and well-being. Dehydroepiandrosterone therapy should be considered in patients whose well-being is greatly impaired even if there is adequate glucocorticoid and mineralocorticoid replacement. A single oral dose in the morning is enough to maintain the concentrations within normal range. 

7The Long-Term Outlook

If cortisol levels are left unchecked, Addison’s disease can lead to adrenal crisis.
This is potentially fatal. Thus, patients need to be educated about the importance of increasing glucocorticoid doses when in stressful situations. Anticipating stressful scenarios is one of the keys to a better prognosis. The outlook for patients with Addison’s disease is generally good, as long as adequate replacement therapy is provided. There are instances, however, where the patient’s quality of life may suffer from having low circulating glucocorticoids. In these instances, therapy with dehydroepiandrosterone is recommended, especially in women and children.

The prognosis for patients with Addison’s disease is good. With proper therapy, many of those suffering from primary adrenal insufficiency can lead normal lives. Therefore, early detection, diagnosis, and treatment are necessary in order to ensure that the quality of life of individuals with Addison’s disease is not diminished. Aside from this, the outlook for people with this disease is a complete resolution of symptoms once therapy has been initiated at the proper dose and time.