Introduction

Adrenal Insufficiency (AI) defines an inadequate secretion of cortisol or aldosterone or both hormones. At the same time the clinical picture can be highly variable and anyone presented with unexplained fatigue, hyponatraemia or hypertension should be subjected to suspicion of AI by the clinician(1). The disease is classified in such a way that the hypofunction of the adrenal gland is divided in to primary and secondary by cause (2). Either way all types of AI’s are only concerned with the adrenal cortex as the adrenal medullary hormones are not essential for life(3). The patterns of the disease are usually considered as three main conditions (2).
(i) Primary acute adrenocortical insufficiency also known as adrenal crisis.
(ii) Primary chronic adrenocortical insufficiency or Addison’s disease (AD).
(iii) Secondary AI or a decreased stimulation of adrenals owing to a deficiency of Adrenocorticotrophic hormone (ACTH).

The Adrenal Gland
Adrenal Anatomy
Adrenal gland is an important endocrine gland in the body weighing 8-10gm s. It contains a steroid-producing cortex which (4, 5) has a mesodermal origin from the peritoneal lining. The other part is the catecholamine producing medulla, which originate from neural crest cells and resemble modified sympathetic ganglion cells (4, 5). The gland is located on the superomedial surface of the corresponding kidney and is covered by the same fascial sheath that covers the kidney known as the renal fascia. The kidney is separated from it by a little fatty connective tissue layer. The right gland is pyramidal in shape and the left is crescent shaped. The renal arteries, aortic branches and inferior phrenic arteries supply it, first the cortex then through the cortex to the medulla. The right is drained directly to inferior vena cava as the right suprarenal vein, and the left to the left renal vein (5). The cortex consist of 3 zones (4)

The outermost Zona glomerulosa which principally secretes mineralocorticoids, mainly aldosterone(6). It is also the sole aldosterone producer in the body (4) aldosterone secretions is independent of ACTH (Adrenocorticotrophic hormone) produced by the anterior pituitary in response to CRH (corticotrophin releasing hormone) produced in the hypothalamus (6)

The next zone is zona fasciculata the middle and broadest of the zones. Secretes glucocorticoid hormones of which the main form is cortisol. Its secretion unlike aldosterone which is independent at ACTH, is solely regulated by hypothalmopituitary adrenal axis. This layer also secretes a small amount of adrenal androgens and estrogens (7)

The innermost zone is zona reticularis and it produces some amount of glucocorticoid and also adrenal androgens. Though its width is the thinnest of the 3 zones, varies under different physiological conditions to which it is subjected (6)
Physiology of Adrenocortical hormone secretion

The anterior pituitary hormone ACTH is a principal stimulator of the adrenocortical hormone out put. About 20% anterior pituitary cells are corticotropes that secrete ACTH (8). The main ACTH activity is aimed at the production at Glucocorticoids. The levels of cortisol have a negative feed back action on the anterior pituitary and the hypothalamus. Reduced levels of blood cortisol will stimulate the hypothalamus to produce CRH. CRH is also released in response to the circadian rhythm and stress. In response to CRH and also direct stimulation of anterior pituitary by a low cortisol level in blood causes ACTH to be released (4). Circulating ACTH stimulates cortisol production in the adrenals. Cortisol will in turn cause negative feed back on both hypothalamus and pituitary that will regulate the release of CRH and ACTH accordingly. The set point of this system has a direct variation pattern to the circadian rhythm which can be overridden by stress (4, 3, 9). Secretion of Aldosterone and mineralocorticoids is mainly regulated by the renin angiotensin system. But ACTH is also needed though is not of notable influence (7).But Adrenal sex steroid production is largely independent of pituitary action. (4)

Primary Acute AI

Primary Acute AI or the adrenal crisis can occur in conditions where a patient with chronic AI is subjected to stress thereby precipitating AI and creating a state in which immediate increase in steroid out put is required. But due to chronic AI already suppressing corticosteroid out put, will create the so called crisis. (2) Prolonged administration of anti-inflammatory glucocorticoids suppress the ACTH production of pituitary (3). In patients maintained on such exogenous corticosteroids, a rapid withdrawal or failure to increase the doses in response to acute stress may also precipitate primary acute AI (2) In cases of prolonged glucocorticoid treatment, even if the responsiveness is stimulated by exogenous ACTH, the pituitary may still need as long as a month to reach normal ACTH production (3). Massive adrenal hemorrhage that occurs in cases of newborns, following difficult delivery, in patients under anticoagulant therapy or patients who develop disseminated intravascular coagulation post surgically will cause hemorrhagic infarction of the adrenals and develop primary acute AI (2). It is also noted in a special case where bilateral adrenal hemorrhage causing primary acute AI should also be considered in patients with systemic lupus erythematosus (10). In an over whelming bacterial infection usually associated with Neisseria meningitidis or occasionally by pseudomonas or pneumococci, direct bacterial seeding of small adrenal vessels, development of disseminated intravascular coagulation and endotoxin induced vasculitis (or hypersensitivity vasculitis) will cause adrenal hemorrhage that will develop primary acute AI . This especial condition is called Waterhouse Friderichsen syndrome (2). A normal healthy subject when exposed to a single intra or periarticular injections of corticosteroid for posttraumatic or micro traumatic articular injuries are also at the risk of hypothalmopituitary adrenal axis suppression that can in turn create an acute adrenal crisis (11)

Primary Chronic AI

Primary Chronic AI is called Addison’s disease after Thomas Addison who in 1855 published a paper about some individuals with several symptoms of languor, debility, feebleness of heart action, and peculiar change in the colour of skin. It is an uncommon disease and adrenal cortex is subjected to progressive destruction but clinical manifestations arise when at least 90% of the cortex is demolished (2). Some define it as a destruction of the entire adrenal cortex (4). Pathogenesis of the cortical destruction in more than 90% of all cases is by autoimmune adrenalitis, tuberculosis (TB), the acquired immune deficiency syndrome (AIDS) or metastatic cancer, (2) but lymphomas, amyloidosis, sarcoidosis, hemochromatosis, fungal infections and adrenal hemorrhage can also be the cause. In the U.K. there is marked female preponderance by autoimmune disease (>90% of AI cases) rather than TB (4). In the case of autoimmune adrenalitis adrenal cortex is subjected to organ specific auto antibodies. (eg. 21 hydroxylase as the common antigen). There are also incidents associated with autoimmune conditions like poly glandular autoimmune syndromes type I and II (2, 4 , 12) Type I is inherited as an autosomal recessive condition causing Addisons disease, chronic mucocutaneous candidiasis and hypoparathyroidsm. Type II is more common and apart from developing Addisons disease it may lead to autoimmune thyroid disease, diabetes mellitus and hypogonadism. It is inherited with linkage to the HLA major histocompatibility complex, mainly HLA – DR 3 and DR 4 (12)

In especial cases Addisons disease (AD) was shown to have a positive association with Celiac disease (CD). A study indicates that patients with AD or CD should be independently screened for the other (13). An important factor of primary AI is that usually both glucocorticoid and mineralocorticoid deficiency does not arise in secondary adrenal insufficiency in which an intact renin angiotension aldosteron system will keep up the secretary process intact. (14) The major actions at glucocorticoids are increasing or stimulating :Gluconeogenesis, glycogen deposition, protein catabolism, fat deposition, sodium retentions potassium loss, free water clearance, Uric acid production and circulating neutrophil count. But they inhibit or decrease protein synthesis, host response to infection, lymphocyte transformation, delayed hypersensitivity, circulating lymphocyte count and circulating eosinophil count (4) In AD, glucocoticoid & mineralocorticoid reduction will lead to symptoms such as weight loss, Anorexia, malaise, weakness, fever, depression, impotence, amenorrhoea, nausea, vomiting, diarrhea, confusion ,syncope from postural hypotension , abdominal pain, constipation, myalgia, joint or back pain and muscle cramps. Signs of AD include pigmentation, buccal pigmentation postural hypo tension, weight loss, wasting dehydration and vitiligo (4) The adrenal crisis is often precipitated by other disease, surgery and infections(1). In AD mineralocorticoid deficiency is mainly the lack of aldosterone so renal tubular sodium reabsorption decreases and Na+ water and chloride ions are greatly lost in urine. So there will be a general decrease in extra cellular fluid volume, thus the plasma volume falls with and increase of red cell concentration and a decrease of cardiac out put. Death can arise by hypovolemic shock. If untreated death arises within 4 days to 2 weeks after aldosterone levels have depleted (7). But Glucocorticoid deficiency is mainly based on the lack of Cortisol which means the normal blood glucose concentration between nutritional intake is not maintainable by Gluconeogenesis. The mobilization of protein & fat is also reduced by the lack of Cortisol. Therefore there is a general slowing of metabolism throughout the body (7). The most significant differentiating factor of AD from secondary AI is skin pigmentation (12). Pigmentation occurs in scars that developed after the onset of the disease, in skin creases and nipple areolas, at pressure points and also in gums (3) .The pigmentation can be detectable in the form of diffuse tanning and also in a form at spotty pigmentation.(3) This is a general symptom of chronic glucocorticoid deficiency (3). The reason is based on the fact that ACTH shares the precursor prehormone which is proopiomelanocortin, with several other endocrine peptides including melanocyte stimulating hormone (MSH), β – lipoprotein and β – endorphin (7). Therefore when AD causes a decrease in Blood cortisol levels the negative feed back loop stated earlier (4) will act on both hypothalamus and pituitary so that as a final result of the feed back stimulation, ACTH level will be greatly increased. As the cortex has been considerably destroyed or totally demolished by AD, the feed back stimulation to produce ACTH will continue. Thus ACTH will start acting in a MSH like manner. Melanocytes will be stimulated. This melanin is not always deposited, but the deposition will occur in the areas mentioned above (3) where thin skin maybe found. But some point out that this pigmentation also occur because CRH will not only stimulate ACTH but also MSH. Therefore to a lesser degree of pigmentation is due to actual MSH but mainly due to MSH like activity of elevated ACTH. (7, 14). When primary AI strikes an individual morphological impact varies according to the pathogenesis. For example if it is due to primary autoimmune adrenalitis the glands are shrunken and will be difficult to identify within suprarenal adipose tissue. A variable lymphoid invasion may reach the medulla but usually it is preserved. (2) But if the case is due to tuberculosis and fungal disease the adrenal composition is challenged by a granulomatous inflammatory reaction, which is usually seen in sites of infections. Or if it is a case of metastatic carcinoma the infiltrating neoplasm will rather enlarge the adrenals contrary to primary autoimmune adrenalitis in which case the glands are shrunken .(2)

Secondary hypoadrenalism

Secondary AI or secondary hypoadrenalism is most often due to a sudden cessation of exogenous glucocorticoids used as therapy. (4, 12) As mentioned earlier primary acute AI can also be precipitated by abrupt withdrawal of exogenous glucocorticoids (9) But in the case of secondary AI the AI is totally due to the lack of ACTH but not a disorder concerned with the actual steroid production of the adrenal cortex (12) Such therapy of exogenous glucocorticoid suppress the hypothalamic pituitary adrenal axis and with the lack of ACTH will lead to adrenal atrophy which sometimes last for months after withdrawal of glucocorticoid treatment (4, 12) This can be expected in anyone who has taken more than the equivalent amount of 30 mg of oral hydrocortisone per day (7.5 mg /day of prednisolone or 0.75 mg/day of dexamethasone) for longer than a month (12) With reference to the circadian rhythm (3, 4, 9) the timing of the dose may also affect the degree at adrenal suppression (12) So prednisolone 5 mg at night and 2.5 mg in the morning will be extremely more prominent in hypothalmopituitary suppression than that caused by the 5 mg in the morning and 2.5 mg at night. (12) Most patients with this form of suppressed hypothalmopituitary axis may also have panhypopituitarism and will need Thyroxin replacement as well as cortisol. But cortisol replacement should be started earlier than Thyroxin replacement. (4). Any disorder of the hypothalamus and pituitary can generate secondary AI. Common disorders are metastatic cancer, infection, infarction or irradiation and the general cause of secondary AI is the reduction in the ACTH out put. (2) Contrary to AD there is no skin pigmentation. Also notable is the fact that aldosterone out put is normal or near normal owing to the fact that there is a zona glomerulosa in the cortex to respond to the renin angiotensin system. (2) Therefore in secondary AI marked hyponatraemia and hyperkalemia is not seen. (2) The ATCH deficiency as stated above can (4) be isolated or associated with panhypopituitarism or rather multiple primary trophic hormone deficiencies (2) Another factor of differentiating AD form secondary AI is the fact that ACTH exogenously administered can increase plasma levels at cortisol (9) The differences in salt and water balance in the two groups of AI is a significant factor that changes the clinical presentation (12). Therefore in the case of Secondary AI due to hypopituitarism the ACTH deficiency is also associated with the deficiencies of Luteinizing hormone (LH) follicle stimulating hormone (FSH) Thyroid stimulating hormone (TSH) and growth hormone(GH) Therefore the deficiencies of GH will cause hypoglycemia and of TSH will cause weight gain and cold intolerance and of FSH, LH will cause infertility, oligo/amenorrhoea and poor libido. But if it is isolated ACTH deficiency like in the case of exogenous glucocorticoid withdrawal, then the features are more of chronic AI or AD without any signs of pigmentation. (12). The size of the adrenals will vary according to the lack of ACTH (2) It could be a moderate or marked reduction . Even if reduced to small flattened structures the cortex retains the yellow colour because an amount of lipid will be left over. The main composition of the active cortex at this stage will be the glomerulous zone where the renin angiotensin axis will maintain aldosterone production (2).

Investigation of AI

There are several main investigations aimed at AI which are routine biochemical profiles which involves assessment of plasma, potassium, blood urea and blood glucose. Then more specific AI oriented investigations like plasma cortisol /ACTH test, testing mineralocorticoid status and stimulation tests. (12)

Routine biochemical profile

Measurement of plasma electrolytes may give the first clue of diagnosis in AD that has been there for an established period of time. Hyponatraemia can be expected in 90% of the cases. But Hyperkalemia is found in 65%. The blood urea level is increased. In secondary AI dilutional or low blood urea maybe found. When diagnosing secondary AI in this way a rise in Eosinophil count and an elevated ESR may also assist as pointers. In more than half of those who suffer from primary or secondary AI , hypoglycemia is detected (12, 14)

Plasma Cortisol / ACTH

Basal plasma cortisol and urinary free cortisol levels are often in the low normal range and cannot be used to exclude the diagnosis. The test directly aimed at primary AI or AD is simultaneous measurement at plasma cortisol and ACTH, so that a disproportionate elevation of ACTH to cortisol can be observed. Then the cortisol response to exogenous ACTH is also useful. (This will be disused later) (12, 14) A random cortisol level below 100 n mol/L is suggestive of AI but > 550 n mo/L is unlikely (4) A 0900h in plasma ACTH > 80 ng/L with low or low normal cortisol confirms primary AI (4)

Mineralocorticoid status

The difference of aldosterone level in the case of Primary and secondary AI is of great value in differentiating the disease condition (2) Therefore in the case of primary AI the renin activity in Plasma is elevated and the plasma aldosterone is low or normal (12)

Stimulation Tests

The stimulation test is most commonly ACTH stimulation. This involves intravenous or intramuscular injection of 250 mg of tetracosactrin (Synacthen) Then the Plasma cortisol level is measured immediately, after half and hour and also after one hour. During the half hour measurement a normal person will indicate at least 550 nmol/L of cortisol. In all forms of AI, less than the 550 mark can be found after acute administration of Synacthen. Measuring ACTH as discussed earlier can differentiate the two forms of AI. Another way to differentiate between the two forms of AI is by performing prolonged stimulation test. This test is performed by administrating an intramuscular dose of 1 mg de pot tetracosactrin with measurement of plasma cortisol at 0, 4 and 24 h. Normally at the mark of 4 h, cortisol is > 1000nmol/L and 24 h is a little increased than that. People with AD will show instead a significant increase in the 24 h mark. (14) The insulin tolerance test is also a useful investigation on assessing both ACTH and GH reserves. But it cannot be performed on people with ischemic heart problems, epilepsy or hypopituitarism (severe) (14). The test is performed by intravenously administering soluble insulin 0.1 to 0.15 U/kg of body weight, than plasma cortisol is measured at 0, 30, 45, 60, 90, 120 min. Hypoglycemia with blood glucose <2.2mmol/L and neuroglycopenia, sweating, tachycordia is essential. Normally the cortisol peak exceeds 500 nmol/L. This test is useful to be performed after an ACTH stimulation test that showed a positive of AI and not otherwise. (14) This is because some patients hold an inadequate response to ACTH but normal response to hypoglycemia and does not require corticosteroid replacement therapy. (14)

Other tests

Antibodies against 21 hydroxylase antigen can be detected via radioimmunoassay in order to confirm AD. Also in AD it is important to look for signs of organ specific autoimmune disease (14). Chest and abdominal x-rays may show evidence of tuberculosis and calcified adrenal glands (4) CT and MRI scanning is useful in detecting adrenal hemorrhage or neoplasm, but CT is better in making out the difference between an inflamed adrenal from a metastasized (14)

Treatment for AI

If a patient is suspected of AD investigation is a prompt action. A seriously afflicted individual with hypertension, an intramuscular hydrocortisone (100 mg) with intravenous saline is a good protective measure (4). An acute AI patient is for the emergency room. If his/her cardiovascular function is normal 1L of normal saline over 30-60 min with 100 mg of intravenous bolus hydrocortisone is the standard 1st approach. The next step is administering several liters of saline up to the next day, with six hourly hydrocortisone
(100mg) intramuscularly, till the individual is stable. The hypoglycemic, need glucose infusion. Then an oral replacement can be started, firstly hydrocortisone 20 mg, then reducing over a few days. (4,14). As hydrocortisone also holds sufficient mineralocorticoid activity mineralocorticoids are not necessary at this stage but when hydrocortisone dose is reduced in cases of acute AI then fludrocortison acetate is useful in doses of 0.05 – 0.1 mg daily(14). As noted before those with primary AI may require both glucocorticoid and mineralocorticoid replacement. But when it comes to secondary AI only glucocorticoids are needed. In case of chronic replacement therapy for both AI conditions the daily glucocorticoid dose is 30 mg of hydrocortisone per day in such a way that 20 mg on waking up and 10 mg at six noon. The actual amount may vary from individual to individual. If inadequate then primary AI patient (AD) will still hold pigmentation and elevation of ACTH. In events of intercurrent febrile illness, trauma, mental stress, the dose of glucocorticoids must be doubled. In cases of vomiting, paraentaral infusion is urgent. In case of surgery 100 mg hydrocortisone hemisuccinate is given with the premedication. Even in major operations this is conducted together with the procedure taken for acute AI. If an individual is given enzyme inducing drugs like Rifampicin or Phenytoin then the hydrocortisone dose need increasing. The same goes with pregnancy. This is because in gestation estrogen increase cortisol binding globulin thus free cortisol will decrease(14). A famous clinical practice on patients with glucocorticoid therapy is to get them registered for a Medic-Alert bracelet or necklace and making them carry a Steroid Card (5,3) In case of postural hypotension and hyperkalaemia, “fludrocortisone” is useful and it’s need can be monitored simply by measuring blood pressure or plasma electrolytes.(4, 14)

Discussion
All forms of AI hold a considerable risk of death and impairment of a normal lifestyle.
( 4 , 7 , 12) So as suggested above the patient who shows up with typical signs of AI should be screened immediately while the first hand treatment line is commenced. AIDS, TB and other forms of pathological conditions are also capable of generating AI. So screening such an individual for AI is important. (2, 4, 12, 10, 13) when it comes to treating an individual for AI the administration of medications should be carefully regulated and in the case of an adrenal crisis, prompt action is essential. (4). In the process of diagnosis utmost importance rest on the differentiation of one form of AI from another . The physiologic regulation and the influence of the adrenal gland in general can always be applied to classify, diagnose, investigate and finally treat all forms of AI. (4, 3, 9).

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