Sandbox:Aditya

Epidemiology

Incidence

United States The prevalence of Addison disease is 40-60 cases per 1 million population.

Mortality/Morbidity

Morbidity and mortality associated with Addison disease usually are due to failure or delay in making the diagnosis or a failure to institute adequate glucocorticoid and mineralocorticoid replacement. [6] If not treated promptly, acute addisonian crisis may result in death. This may be provoked either de novo, such as by adrenal hemorrhage, or in the setting of an acute event superimposed on chronic or inadequately treated adrenocortical insufficiency. With slow-onset chronic Addison disease, significant low-level, nonspecific, but debilitating, symptomatology may occur. Even after diagnosis and treatment, the risk of death is more than 2-fold higher in patients with Addison disease. Cardiovascular, malignant, and infectious diseases are responsible for the higher mortality rate. [7] White and Arlt examined the prevalence of and risk factors for adrenal crisis in patients with Addison disease, utilizing a survey of Addison patients in the United Kingdom, Canada, Australia, and New Zealand. The authors' results indicated that approximately 8% of patients diagnosed with Addison disease require annual hospital treatment for adrenal crisis. In addition, the investigators concluded that exposure to gastric infection is the most important risk factor for adrenal crisis in the presence of Addison disease; diabetes and/or asthma [8] concomitant with Addison disease also increase the risk, according to White and Arlt. [9] A study by Chantzichristos et al indicated that in patients with type 1 or 2 diabetes, those who also have Addison disease have a higher mortality rate than do those with diabetes alone. Over a median follow-up period of 5.9 years, the mortality rate for diabetes patients with Addison disease was 28%, compared with 10% for those without Addison disease. The increase in the estimated relative overall mortality risk was 3.89 for the Addison disease patients compared with the other group. Although cardiovascular deaths accounted for the highest mortality rate in both groups, the death rate from diabetes complications, infectious diseases, and unknown causes was greater in the patients with Addison disease than in those with diabetes alone. [10]

Race

Addison disease is not associated with a racial predilection.

Sex

Idiopathic autoimmune Addison disease tends to be more common in females and children.

Age

The most common age at presentation in adults is 30-50 years, but the disease could present earlier in patients with any of the polyglandular autoimmune syndromes, congenital adrenal hyperplasia (CAH), or if onset is due to a disorder of long-chain fatty acid metabolism.

Classification

Adrenal insufficiency disorders may be classified into acute and chronic forms, depending on the timing of presentation and duration and into primary and secondary, depending on the etiology of adrenal insufficiency.

Based on the duration of symptoms

Acute adrenal insufficiency

• Adrenal crisis

Chronic adrenal insufficiency

• Chronic primary adrenal insufficiency
• Chronic secondary adrenal insufficiency

Based on etiology

Primary adrenal insufficiency(Addisons disease)

• Anatomic destruction of the adrenal gland
• Infection (TB)
• Congenital adrenal hyperplasia

Secondary adrenal insufficiency

• Hypothalamic-pituitary axis suppression

Pathology

Cortisol is normally produced by the adrenal glands, which are located just above the kidneys. It belongs to a class of hormones called glucocorticoids, which affect almost every organ and tissue in the body. Scientists think that cortisol possibly has hundreds of effects in the body. Cortisol's most important job is to help the body respond to stress. Among its other vital tasks, cortisol;

Helps maintain blood pressure and cardiovascular function Helps slow the immune system's inflammatory response Helps balance the effects of insulin in breaking down sugar for energy Helps regulate the metabolism of proteins, carbohydrates, and fats Helps maintain proper arousal and sense of well-being Because cortisol is so vital to health, the amount of cortisol produced by the adrenals is precisely balanced. Like many other hormones, cortisol is regulated by the brain's hypothalamus and the pituitary gland, a bean-sized organ at the base of the brain. First, the hypothalamus sends "releasing hormones" to the pituitary gland. The pituitary responds by secreting hormones that regulate growth, thyroid function, adrenal function, and sex hormones such as estrogen and testosterone. One of the pituitary's main functions is to secrete ACTH (adrenocorticotropin), a hormone that stimulates the adrenal glands. When the adrenals receive the pituitary's signal in the form of ACTH, they respond by producing cortisol. Completing the cycle, cortisol then signals the pituitary to lower secretion of ACTH.

Aldosterone Aldosterone belongs to a class of hormones called mineralocorticoids, also produced by the adrenal glands. It helps maintain blood pressure and water and salt balance in the body by helping the kidney retain sodium and excrete potassium. When aldosterone production falls too low, the kidneys are not able to regulate salt and water balance, causing blood volume and blood pressure to drop.

Laboratory

Evaluating a patient with suspected adrenal insufficiency is a three-step process: establishing the diagnosis, differentiating between primary and secondary adrenal insufficiencies, and looking for the cause of adrenal insufficiency.

8 am cortisol

>15Ug/dL

3-15Ug/dL

<3Ug/dL

Adrenal insufficiency is ruled out

Measure ACTH

30 min cortisol during cosyntropin stimulation test

>18Ug/dL

<18Ug/dL

Adrenal insufficiency is ruled out

Adrenal insufficiency confirmed

Measure ACTH

Low/normal

Elevated

Secondary Adrenal insufficiency

Primary Adrenal insufficiency

Adrenal crisis=

Supportive Therapy

• IV access should be established immediately with an infusion of isotonic sodium chloride solution should be begun to restore volume deficit and correct hypotension.

Mecial Management

• Preferred regimen (1): Dexamethasone sodium phosphate 4 mg iv q24h
• Preferred regimen (2): Hydrocortisone sodium succinate 50-100 mg iv q8h
• Note: Infusion may be initiated with 100 mg of hydrocortisone as an IV bolus with saline and infuse over 24 h to avoid needing to renew the infusion every 8-10 hours.

The infusion method maintains plasma cortisol levels more adequately at steady stress levels, especially in the small percentage of patients who are rapid metabolizers and who may have low plasma cortisol levels between the IV boluses. Clinical improvement, especially blood pressure response, should be evident within 4-6 hours of hydrocortisone infusion. Otherwise, the diagnosis of adrenal insufficiency would be questionable. After 2-3 days, the stress hydrocortisone dose should be reduced to 100-150 mg, infused over a 24-hour period, irrespective of the patient's clinical status. This is to avoid stress gastrointestinal bleeding. As the patient improves and as the clinical situation allows, the hydrocortisone infusion can be gradually tapered over the next 4-5 days to daily replacement doses of approximately 3 mg/h (72-75 mg over 24 h) and eventually to daily oral replacement doses, when oral intake is possible. As long as the patient is receiving 100 mg or more of hydrocortisone in 24 hours, no mineralocorticoid replacement is necessary. The mineralocorticoid activity of hydrocortisone in this dosage is sufficient. Thereafter, as the hydrocortisone dose is weaned further, mineralocorticoid replacement should be instituted in doses equivalent to the daily adrenal gland aldosterone output of 0.05-0.20 mg every 24 hours. The usual mineralocorticoid used for this purpose is 9-alpha-fludrocortisone, usually in doses of 0.05-0.10 mg per day or every other day. Patients may need to be advised to increase salt intake in hot weather.

hese drugs are used for replacement therapy in Addison disease and secondary adrenocortical insufficiency. [3, 4] Prednisone (Deltasone, Sterapred, Orasone)

View full drug information Used for glucocorticoid hormone replacement. Longer acting than hydrocortisone, with a biologic half-life of 18-36 h. Fludrocortisone (Florinef)

View full drug information Synthetic adrenocortical steroid with very potent mineralocorticoid activity. For use in Addison disease and states of aldosterone deficiency. Hydrocortisone sodium succinate or phosphate (Cortef, Hydrocortone)

View full drug information Drug of choice for steroid replacement in acute adrenal crisis and for daily maintenance in patients with Addison disease or secondary adrenocortical insufficiency. Has both glucocorticoid and mineralocorticoid properties. Biologic half-life is 8-12 h. Easiest way to set up infusion is to have pharmacy mix 100 mg of hydrocortisone in 100 mL of 0.9 saline.

Surgery

Parenteral steroid coverage should be used in times of major stress, trauma, or surgery and during any major procedure. During surgical procedures, 100 mg of hydrocortisone should be given, preferably by the IM route, prior to the start of a continuous IV infusion. The IM dose of hydrocortisone assures steroid coverage in case of problems with the IV access. When continuous IV infusion is not practical, an intermittent IV bolus injection every 6-8 hours may be used. After the procedure, the hydrocortisone may be rapidly tapered within 24-36 hours to the usual replacement doses, or as gradually as the clinical situation dictates. Mineralocorticoid replacement usually can be withheld until the patient resumes daily replacement steroids. Addison’s disease (also known as primary adrenal insufficiency or hypoadrenalism) is a rare disorder of the adrenal glands. It affects the production of two essential hormones called cortisol and aldosterone.

Risk Factors

Common risk factors in the development of polycystic ovary syndrome are

• Hyperinsulinemia secondary to insulin resistance; associated with type 2 diabetes mellitus
• Obesity
• Family history of PCOS among first-degree relatives

Associated Conditions

Common conditions associated with PCOS are

• Type 2 diabetes
• Endometrial hyperplasia and cancer
• Infertility
• Hypertension
• Gestational diabetes
• Preeclampsia
• Hirsutism
• Acne

History

Obtaining the history is the most important aspect of making a diagnosis of PCOS. It provides insight into the cause, precipitating factors and associated comorbid conditions.

• Menstrual abnormalities
• Infertility
• Signs of virilization on physical examination
• Family history of PCOS among first-degree relatives

Symptoms

The most common symptoms of PCOS include

• Amenorrhea or oligomenorrhea
• Abnormal uterine bleeding
• Androgenization, including hirsutism (often slowly progressive), acne, oily skin (common)
• Polycystic ovaries, with or without ovarian enlargement
• Insulin resistance
• Endometrial hyperplasia

Laboratory Findings

Measurement of the plasma levels of several hormones is helpful in supporting the diagnosis of PCOS and especially in excluding other disorders. Determining the LH/FSH ratio of 3:1 is virtually diagnostic of PCOS; however, a normal ratio does not exclude the diagnosis, as LH levels fluctuate widely throughout the course of a day. Other androgens are measured to screen for other virilizing adrenal tumors. Fasting blood glucose is measured to look for diabetes; screening for lipid abnormalities is also employed. Testosterone is measured to exclude a virilizing tumor. Prolactin is measured to exclude a prolactinoma. Thyroid-stimulating hormone (TSH) is measured to rule out hypothyroidism

Harmone		Normal value	PCOS Laboratory Findings
LH/FSH ratio		<3;1	A ratio >3:1 (>2.5:1 according to some) is indicative of PCOS
Testosterone		Free: 100 to 200 pg/dL Total: 20 to 80 ng/dL	An elevated free testosterone level (200-400 pg/dL) is suggestive of PCOS,
Prolactin		3.8 to 23.2 μg/L	A level >300 μg/L is virtually diagnostic of prolactinoma.
TSH		0.4 to 4.2 mIU/L	Levels are normal in patients with PCOS
Androgens	Sex hormone–binding globulin
	Androstenedione:	75 to 205 ng/dL
	Estrone:	1.5 to 25.0 pg/mL
	Dehydroepiandrosterone sulfate:	50 to 450 μg/dL
	17-Hydroxyprogesterone (follicular phase):	15 to 70 ng/dL