Primary Adrenal Insufficiency: Addison’s DiseaseAshleigh Alderson, John Cossey, Neil Dodsworth, Timothy Down, Kayleigh Hughes

Adrenal Insufficiency

Adrenal Glands

Small, approximately 6 gram, glands located on top of the kidneys.

Secrete hormones into circulation: Adrenal Cortex (General divisions, in reality more complicated)

Glomerulosa: Mineralocorticoids Fasciculata: Glucocorticoids Reticularis: Glucocorticoids and androgens

Adrenal Medulla Chromaffin cells: Adrenaline and noradrenaline

Adrenal Function

Addison's Disease

Name refers to a condition brought on by adrenal insufficiency.

Under some circumstances, glucocorticoid and mineralocorticoid production can stop or decrease. Caused by destruction/dysfunction in the adrenal cortex or

deficient ACTH secretion in the pituitary.

Addison's Disease: Pathophysiology Symptoms of adrenocortical insufficiency arises when less

than 10% of cortex remains. Development can be quick or slow, but diagnosis usually occurs

around the time of a crisis. Period of stress can increase symptoms.

Pathophysiology: Mineralocorticoids

Mineralocorticoids normally: Stimulate excretion of K Stimulate reabsorbtion of Na

Deficiency in mineralocorticoids leads to low levels of Na and high levels of K: Dehydration Hypertonicity Acidosis Hypotension

Pathophysiology: Glucocorticoids With the adrenal glands failing, the body will be unable to

produce glucocorticoids. Normally glucocorticoids:

Stimulate carbohydrate, protein and fat metabolism. Suppress inflammation and release of pituitary hormones.

A lack of glucocorticoids leads to: Hypotension, hypoglycemia, insulin sensitivity, altered

metabolism, stress resistance lowered, dehydration, weakness and increased pituitary function.

Addison's Disease: Causes

Primary: Autoimmune Adrenocortical Insufficiency Adrenal Hemorrhage Infection Adrenoleukodystrophy Metastatic Adrenal Disease AIDS Cortisol resistance Familial glucocorticoid deficiency.

Signs and Symptoms Common symptoms of Adrenal Insufficiency:

Loss of Weight. Low Blood Pressure (Orthostatic Hypotension) Vomiting. Nausea. Diarrhoea. Painful Muscles and Joints. Disorientation. Hyperglycaemia.

Unspecific Symptoms. Not until an Addisonian Crisis occurs that Addison's

Disease is Suspected.

Signs and Symptoms Addisonian Crisis:

Sudden Pain- Legs/ Lower back or Abdomen. Syncope (Sudden Loss of Consciousness) Hypoglycaemia. Dehydration. Hyperkalaemia. Convulsions. Fever.

Addison's Disease- Not usually apparent until over 90% of the adrenal cortex is destroyed. (Primary Adrenal Sufficiency)

Salt Craving Skin Pigmentation. Pinna Calcified.

Hyperpigmentation

Over production of Melanin in Skin: ACTH shares the same pre-cursor molecule (Pro-opiomelanocortin).

Physical Examination Medical History. Skin Examination- Hyperpigmentation. Your blood pressure when you are lying down and

sitting up. Your skin and your weight, for signs of excess fluid loss. Absence of axillary and pubic hair and decreased body

hair. (↓ Androgens in Women) Patients show evidence of dehydration, hypotension,

and orthostasis.

Preliminary Blood Tests Initially a blood sample will be taken from the patient

and a number of parameters are measured: Potassium Levels (Hyperkalaemia) Sodium Levels (Hyponatremia) Cortisol Test. CRH Levels (Corticotrophin) (↑) ATCH (Adrenocorticotropic hormone) (↑) Metabolic Acidosis.

Autoimmune Addison’s Disease: Auto Antibodies (21-hydroxlase autoantibodies) Immunofluorescence. Additionally- Eosinophilia/ Lymphocytosis.

Preliminary Urine Tests Along side blood testing a urine test is also

undertaken to again check for certain parameters: Sodium Levels (Hypernatremia) Cortisol Test. Aldosterone Levels (↓) Kidney function tests- Concentrated Urine.

A BUN (Blood Urine Nitrogen) Test or Creatinine test is sometimes untaken to test kidney function which may be impaired during Addison’s Disease.

Stimulation Tests If Addison's disease is suspected, an additional

test is necessary to confirm the diagnosis.

ACTH Stimulation Tests Short ACTH Stimulation Tests:

High-Dose Low-Dose

Prolonged ACTH Stimulation Tests: Eight-hour Two-day

CRH Stimulation Test

Short ACTH Stimulation Tests Synthetic ACTH is administered intravenously:

250µg for the high dose test 1µg for the low dose test

Serum cortisol and urine cortisol is measured at 0, 30 and 60 minutes.

The normal response after an ACTH injection is a rise in serum and urine cortisol levels.

People with Addison’s disease or long-standing secondary adrenal insufficiency have little or no increase in cortisol levels.

Short ACTH Stimulation Tests (Continued)

Whether a low or high dose ACTH stimulation test may be used is dependent on the suspected cause of the adrenal insufficiency.

The advantage of a high-dose is that it can also be injected intramuscularly.

But if secondary adrenal insufficiency is mild or of recent onset, the adrenal glands may still respond to ACTH because they have not yet atrophied.

The low dose seems more reliable because it can raise cortisol levels in healthy people but not in people with mild or recent secondary adrenal insufficiency.

CRH Stimulation Test A CRH stimulation test can be used to determine the

cause of adrenal insufficiency if the response to the ACTH test is abnormal.

In the test, synthetic CRH is intravenously injected. Serum cortisol is measured before the injection and 30,

60, 90, and 120 minutes after the injection. Patients with Addison’s disease produce high levels of

ACTH but no cortisol in response to the injection. Patients with secondary adrenal insufficiency have

absent or delayed ACTH responses. An absent ACTH response indicates the cause could be the

pituitary. A delayed ACTH response indicates the cause could be the

hypothalamus.

Emergency Diagnosis If an Addisonian crisis is suspected, the patient must

undergo treatment immediately with glucose-containing fluids, salt, and glucocorticoid hormones.

The treatment makes the ACTH and CRH stimulation tests unreliable.

The patient could have to wait for up to a month after the crisis has subsided and the treatment stopped before a reliable diagnosis can be made.

If the diagnosis still remains unclear then other laboratory tests should be performed.

Adrenal Imaging

The ability to use cross-sectional imaging has had a dramatic effect upon the examination of the adrenal glands

Diseases of the adrenal glands may come as a result of hormone deficiency or excess

Diseases may be considered hyperfunctional, diseases with normal adrenal function or adrenal insufficiency.

Adrenal Imaging

Primary adrenal insufficiency (Addisons disease) occurs only after at least 90% of the adrenal cortex has been destroyed.

The radiologic manifestations are dependant upon the cause of adrenal insufficiency.

Normal radiography of the abdomen may reveal calcification commonly seen in tuberculosis or histoplasmosis.

A computerized tomography scan uses a thin X-ray beam to image a specific area of the body. The beam rotates around the area to be imaged and generates a 3D image of the internal structure

Adrenal Imaging

Adrenal Imaging A CT scan of the abdomen is used to check for

abnormalities of the adrenal glands and to measure the size of the glands.

This image may give some insight to the cause of the adrenal insufficiency.

Figure 1 (left): normal adrenal glands as seen in a CT scan.Figure 2 (right): Addisons disease. Adrenal glands appear small and densely calcified .

Adrenal Imaging

Magnetic Resonance Imaging (MRI) is used to image a patients internal structures. A tunnel like structure creates a magnetic field around a patient. Radio waves are sent through the field enabling a 3D image to be constructed by computer

Figure 3 (left): normal adrenal glands as seen in a MRI scan.Figure 4 (right): Addisons disease. Adrenal glands appear enlarged.

Adrenal Imaging

An MRI scan of the abdomen is used to check for abnormalities of the adrenal glands.

In this frontal view a significant size increase of the adrenal glands due to Addisons disease.

Turberculin skin Test Method

Skin disinfected with alcohol TB protein antigen injected under the skin Firm red bump present after 2 days if previous

exposure to TB bacteria

Turberculin skin Test Why complete a tuberculin test?

Tuberculosis can destroy the adrenal glands Less than 20% Mostly used in third world countries

Plasma Renin activity

Method Blood sample taken and analysed Aldosterone and renin ratio calculated

Disease Aldosterone Renin Cortisol

Addisons Disease

Low High Low

Plasma Renin activity Why complete the test?

Cortisol and Aldosterone low Renin activity elevated (increased renal sodium

losses).

Thyroid Function Test

Method Blood sample taken and analysed Thyroid stimulating hormone measured

Why complete the test? Misdiagnosis of patients with Addisons disease-

hypothyroidism (Hussein D et al, 2006)

References ADAM (2009) Diagram of CT and MRI scan [image

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References (cont.) Dunnick, R., (1989) “Adrenal Imaging: Current Status.”, Hanson

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http://www.merckmanuals.com/home/au/sec13/ch164/ch164b.html [Accessed: Monday 28th February 2011]

Grossman, A.B. (2007) Addison's Disease: (Primary or Chronic Adrenocortical Insufficiency)', Available:http://www.merckmanuals.com/professional/sec12/ch153/ch153b.html [Accessed Saturday 26th February 2011)

HealthyNow(2010) Diagram of Kidney and Adrenal Glands [image online], available :http://www.becomehealthynow.com/popups/adrenal_glands1.htm [accessed 15 Feb 2011].

Jeffcoate, W. 1993. Lecture Notes on Endocrinology, 5th Ed., London: Blackwell Scientific Publications.

Leal, A., Bellucci, A., Muglia, V., and Lucchesi, F. (2003) “Unique Adrenal Gland Imaging Features in Addison's Disease Caused by Paracoccidioidomycosis” American Journal of Roentgenology. Vol: 181, pp1433-1434.

References (cont.)

References (Continued) Nagarkatti P , Ghaffar A, (2010) “Immunology: Tolerance and

Autoimmunity” University of South Carolina [Online] Available at: http://pathmicro.med.sc.edu/ghaffar/tolerance2000.htm (Accessed on: Monday 28th February 2011)

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Raffin-Sanson M.L, Keyzer Y, Bertagna X (2003) Proopiomelanocortin, a polypeptide precursor with multiple functions: from physiology to pathological conditions. Institut Cochin [Online] Available at: http://www.eje-online.org/cgi/reprint/149/2/79 [Accessed: 28 February 2011]