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.

The adrenal glands are two small glands that sit on top of the kidneys.

It can affect people of any age, although it's most common between the ages of 30 and 50. It is also more common in women than men.

Early stages symptoms of Addison’s disease are similar to other more common health conditions such as depression or flu. You may experience:

fatigue (lack of energy or motivation) muscle weakness low mood loss of appetite and unintentional weight loss increased thirst Over time, these problems may become more severe and you may experience further symptoms, such as dizziness, fainting, cramps and exhaustion. You may also develop small areas of darkened skin.

Although these symptoms aren’t always caused by Addison’s disease, you should see your doctor if you have them so they can be investigated.

Read more about the symptoms of Addison’s disease and diagnosing Addison’s disease.

Why it happens

The condition is usually the result of a problem with the immune system, which causes it to attack the outer later of the adrenal gland (the adrenal cortex), disrupting production of steroid hormones aldosterone and cortisol. It is not clear why this happens, but it is responsible for 70-90% of cases in the UK.

Other potential causes include conditions that can damage the adrenal glands, such as tuberculosis (TB), although this is uncommon in the UK.

Read more about the causes of Addison’s disease.

Treating Addison's disease

Addison’s disease is treated with medication to replace the missing hormones. You will need to take the medication for the rest of your life.

With treatment, symptoms of Addison's disease can largely be controlled and most people with the condition live a normal, healthy life.

However, there is a risk of a sudden worsening of symptoms called an adrenal crisis. This can happen when the levels of cortisol in your body fall significantly.

An adrenal crisis is a medical emergency. If left untreated it can be fatal. If you or someone you know has Addison’s disease and is experiencing severe symptoms, call for an ambulance.

Read more about treating Addison's disease.

Symptoms

Addison's disease can be difficult to detect at first because early symptoms are similar to symptoms of many other health conditions.

Initial symptoms of Addison's disease can include:

fatigue (lack of energy or motivation) lethargy (abnormal drowsiness or tiredness) muscle weakness low mood (mild depression) or irritability loss of appetite and unintentional weight loss the need to urinate frequently increased thirst craving for salty foods Dehydration can also be an early sign of Addison’s disease. It's caused by the lack of the hormone aldosterone in your body, which is used to regulate the balance of salt and water.

Progressive symptoms

Further symptoms of Addison’s disease tend to develop gradually over months or years. However, additional stress, caused by another illness or an accident for example, may cause your symptoms to suddenly get worse.

You may also experience further symptoms, such as:

low blood pressure when you stand up (postural or orthostatic hypotension), which can cause dizziness and fainting feeling sick (nausea) vomiting diarrhoea abdominal, joint or back pain muscle cramps chronic exhaustion, which may cause depression brownish discolouration of the skin, lips and gums (hyperpigmentation), particularly in the creases on your palms, on scars or on pressure points, such as your knuckles or knees a reduced libido (a lack of interest in sex), particularly in women Symptoms such as sweating and, very occasionally, psychosis](yourmd:/condition/psychosis/introduction) occur but are unusual. Some women may also have irregular periods or miss some periods completely. Children with Addison's disease may experience [puberty later than usual.

Some people with Addison's disease also develop low blood sugar (hypoglycaemia). This can cause symptoms such as difficulty concentrating, confusion, anxiety and even unconsciousness (particularly in children).

If you're experiencing symptoms of Addison's disease, see your doctor so they can diagnose or rule out the condition. These symptoms will usually improve with appropriate treatment.

Read more about diagnosing Addison's disease and treating Addison's disease.

Adrenal crisis

If Addison’s disease is left untreated, the levels of hormones produced by the adrenal gland will gradually decrease in the body. This will cause your symptoms to get progressively worse and eventually lead to a life-threatening situation called an adrenal or Addisonian crisis.

During an adrenal crisis the symptoms of Addison’s disease appear quickly and severely. This could happen when you're already experiencing initial symptoms or without any symptoms at all.

Signs of an adrenal crisis include:

severe dehydration pale, cold, clammy skin sweating rapid, shallow breathing dizziness severe vomiting and diarrhoea severe muscle weakness headache severe drowsiness or loss of consciousness An adrenal crisis is a medical emergency. If left untreated it can be fatal. If you suspect you or someone you know with Addison’s disease is having an adrenal crisis, call for an ambulance.

If an adrenal crisis is not treated, it can lead to a coma and death. There is also a risk your brain will not get enough oxygen if treatment is delayed, which can cause permanent disability.

Causes

Addison's disease develops when the outer layer of your adrenal glands (your adrenal cortex) is damaged, reducing the levels of hormones it produces.

Problems with the immune system

A problem with the immune system is the most common cause of Addison's disease.

The immune system is your body’s defence against infection and disease. If you are ill, your immune system produces antibodies (a special type of protein to destroy disease-carrying organisms and toxins). These antibodies attack the cause of the illness.

However, if you develop a problem with your immune system, it can start to attack your own healthy tissues and organs. This is known as an autoimmune disorder.

Addison’s disease can develop if your immune system attacks your adrenal glands and severely damages your adrenal cortex. When 90% of the adrenal cortex is destroyed, your adrenal glands will not be able to produce enough of the steroid hormones cortisol and aldosterone. Once levels of these start decreasing, you will experience symptoms of Addison’s disease.

It's not clear why some people develop this problem with their immune system, although it can run in families (see below).

Genetics

Research has shown some people with certain genes are more likely to develop autoimmune disorders.

It is not clear how these genes lead to Addison's disease and similar conditions, but it does mean your risk of developing Addison's disease is increased if you or a close family member have another autoimmune condition, such as:

vitiligo - a chronic (long-term) condition that causes pale, white patches to develop on the skin type 1 diabetes - a chronic condition caused by too much glucose in the blood hypothyroidism - an underactive thyroid gland Other causes

Tuberculosis (TB) is the most common cause of Addison's disease worldwide. TB is a bacterial infection that mostly affects the lungs but can also spread to other parts of your body. It can cause Addison’s disease if it damages your adrenal glands.

Other possible causes of Addison’s disease include:

infections - such as those linked to AIDS, or fungal infections a haemorrhage - very heavy bleeding into the adrenal glands, sometimes associated with meningitis or other types of severe sepsis cancer - if cancer cells from elsewhere in your body spread to your adrenal glands amyloidosis - a disease where amyloid, a protein produced by your bone marrow cells, builds up in your adrenal glands and damages them surgical removal of the adrenal glands (adrenalectomy), for example to remove a tumour a genetic defect with your adrenal glands, which means they do not develop properly or cannot produce hormones Diagnosis

In diagnosing Addison’s disease, your doctor will ask about your symptoms and review your medical history.

They are also likely to ask if there is a history of conditions caused by a problem with the immune system (autoimmune disorders) in your family.

Your doctor will examine your skin for any evidence of brownish discolouration (hyperpigmentation). This will be particularly noticeable where your skin creases on your palm or in your elbow, and also on any scars. However, hyperpigmentation does not occur in all cases of Addison’s disease.

You will also be tested for low blood pressure (hypotension); this will probably be measured while you are sitting down and again shortly after you stand up. This is to see whether you have postural or orthostatic hypotension (low blood pressure when you change position).

Blood tests

If Addison’s disease is suspected, blood tests will be carried out to measure the levels of sodium, potassium and the hormone cortisol in your body. A low sodium, high potassium or low cortisol level may indicate you have Addison’s disease.

You may need to see a hospital hormone specialist (endocrinologist) for your blood to be tested for the following:

a low level of the hormone aldosterone a high level of adrenocorticotrophic hormone (ACTH) a low level of glucose (sugar used for energy) positive adrenal antibodies (antibodies designed to attack the adrenal gland) Any of the above could be a sign of Addison’s disease.

Synacthen stimulation test

If cortisol in your blood is low, or your symptoms strongly suggest Addison’s disease, you will need to have a synacthen stimulation test to confirm the diagnosis.

Your doctor may refer you to an endocrinology unit (a unit that specialises in the study of hormones) for the test. How urgently you are referred will depend on how severe your symptoms are.

Synacthen is a man-made (synthetic) copy of the adrenocorticotrophic hormone (ACTH). ACTH is naturally produced by the pituitary gland (a pea-sized gland below the brain) to encourage the adrenal glands to release the hormones cortisol and aldosterone. When synacthen is administered, the adrenal glands should respond in the same way as they would to ACTH, and release cortisol and other steroid hormones into the blood.

A blood sample will be taken and tested for the level of cortisol, before an injection of synacthen is given into your arm. After 30 and 60 minutes, a further blood sample will be taken for cortisol measurement.

If the ACTH level is high, but the cortisol and aldosterone levels are low, it is usually confirmation of Addison’s disease.

Thyroid function test

As well as a synacthen stimulation test, your thyroid gland may also be tested to see if it is working properly.

Your thyroid gland is found in your neck, it produces hormones that control your body's growth and metabolism (the process that turns the food you eat into energy).

People with Addison’s disease often have an underactive thyroid gland (hypothyroidism), where the thyroid gland does not produce enough hormones. By testing the levels of certain hormones in your blood, your endocrinologist (a specialist in hormone conditions) can determine whether you have hypothyroidism.

Scans

In some cases, your specialist may refer you for a scan of your adrenal gland, which could be a computerised tomography (CT) scan or a magnetic resonance imaging (MRI).

Diagnosis during an adrenal crisis

If Addison’s disease is left untreated, it will eventually lead to a situation called an adrenal crisis. This is where the symptoms of Addison’s disease appear quickly and severely.

During an adrenal crisis, there is not enough time to perform a synacthen stimulation test to confirm Addison’s disease.

If possible, blood will be taken and tested for any of the abnormalities listed above. While you are waiting for the results, treatment may be started with steroid injections, and fluids containing salt and glucose.

Read more about treating Addison’s disease.

Treatment

If you have Addison’s disease, you will need to take daily medication to replace the lost hormones. This should ensure you continue to lead a normal life.

In some cases, the underlying causes of Addison’s disease can be treated. For example, tuberculosis (TB) is treated with a course of antibiotics over a period of at least six months.

However, most cases are caused by a problem with the immune system that cannot be cured.

Medication for Addison’s disease

Treatment will usually involve corticosteroid (steroid) replacement therapy for life. Corticosteroid medication is used to replace the hormones called cortisol and aldosterone that your body no longer produces. It is usually taken in tablet form two or three times a day.

In most cases, a medication called [hydrocortisone] is used to replace the cortisol. Other possible medicines are prednisolone or [dexamethasone], though these are less commonly used.

Aldosterone is replaced with a medication called fludrocortisone. Your doctor may also ask you to add extra salt to your daily diet, although if you are taking enough fludrocortisone medicine this may not be necessary. Unlike most people, if you feel the urge to eat something salty, then you should eat it.

In general, the medications used for Addison's disease don't have side effects unless your dose is too high. If you take a higher dose than necessary for a long time, there is a risk of problems such as weakened bones (osteoporosis), mood swings and difficulty sleeping (insomnia).

Living with Addison’s disease

Addison’s disease should not affect your quality of life or how long you live. Your diet, exercise and daily routine can all continue as normal.

You will usually need to have appointments with an endocrinologist every 6-12 months so they can review your progress and adjust your dose if necessary. Your doctor can provide support and repeat prescriptions in between these visits.

As long as you take your medication, the symptoms of Addison’s disease should completely disappear. Failing to take your medication could lead to a serious condition called an adrenal crisis, so you must:

remember to collect your repeat prescriptions keep spare medication as necessary - for example, in the car or at work and always carry some spare medication with you take your medication every day at the right time of day pack extra medication if you are going away - usually double what you would normally need and your injection kit (see below) carry your medication in your hand luggage if you are travelling by plane, with a note from your doctor explaining why it is necessary You could also inform close friends or colleagues of your condition. Tell them about the signs of adrenal crisis and what they should do if you experience one.

Medical alert bracelets

It is also a good idea to wear a medical alert bracelet or necklace that informs people you have Addison’s disease.

After a serious accident, such as a car crash, your body should produce cortisol. This helps you cope with the stressful situation and additional strain on your body that results from serious injury. As your body cannot produce cortisol, you will need a hydrocortisone injection to replace it and prevent an adrenal crisis.

If you are wearing a medical alert bracelet it will inform any medical staff that may need to treat you about your condition, and what medication you require.

Medical alert bracelets or necklaces are pieces of jewellery engraved with your medical condition and an emergency contact number. They are available from a number of retailers. Ask your doctor if there is one they recommend.

If you need to stay in hospital, the healthcare professionals responsible for your care will also need to know that you need steroid replacement medication throughout your stay.

Adjusting your medication

At certain times, your medication may need to be adjusted to take into account any additional strain on your body. For example, you may need to increase the dosage of your medication if you experience any of the following:

an illness or infection - particularly if you have a high temperature of 37.5C (99.5F) an accident, such as a car crash an operation, dental or medical procedure (such as a tooth filling or endoscopy) you are taking part in strenuous exercise not usually part of your daily life This will help your body cope with the additional stress. Your endocrinologist will monitor your dosage and advise about any changes. Over time, as you get used to the condition and learn what can trigger your symptoms, you may learn how to adjust your medication yourself. However, always consult your doctor or specialist if you are unsure.

Emergency treatment

You and a partner or family member may be trained to administer an injection of hydrocortisone in an emergency.

This could be necessary if you go into shock after an injury, or if you experience vomiting or diarrhoea and are unable to keep down oral medication. This may occur if you are pregnant and have morning sickness. Your endocrinologist will discuss with you when an injection might be necessary.

If you need to administer emergency hydrocortisone, always call your doctor immediately afterwards.

You can also register yourself with your local ambulance service, so they have a record of your requirement for a steroid injection or tablets, if you need their assistance.

Treating adrenal crisis

Adrenal crisis, or Addisonian crisis, needs urgent medical attention. Call for an ambulance if you are (or someone you know is) experiencing adrenal crisis.

Signs of an adrenal crisis include:

severe dehydration pale, cold, clammy skin sweating rapid, shallow breathing dizziness severe vomiting and diarrhoea severe muscle weakness headache severe drowsiness or loss of consciousness In hospital, you will be given lots of fluid through a vein in your arm to rehydrate you. This will contain a mixture of salts and sugars (sodium, glucose and dextrose) to replace those that your body is lacking. You will also be injected with hydrocortisone to replace the missing cortisol hormone.

Any underlying causes of the adrenal crisis, such as an infection, will also be treated.