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The Aetiology and Pathogenesis of Addisons Disease

Updated on April 1, 2015
Thomas Addison
Thomas Addison | Source

Physiology is the study of the normal, healthy functions of the body, from the Greek physis, meaning 'nature', and logia, meaning 'study' (Sherwood, 1997). A disease state is a state whereby these functions are altered and impaired, pathophysiology is the study of these disturbances, and incorporates pathology, the diagnosis and study of disease, from the Greek pathos, meaning 'suffering' (Makins, 1993). The pathophysiology of a disease can essentially be broken down into two stages, the aetiology, or study of the cause, from the Greek aetia, meaning 'cause', and the pathogenesis, the study of the development of disease (Makins, 1993). Disease can also be described as acute, where the onset is rapid, and chronic where the pathogenesis is more sustained. A disease or specific effect of a disease can also be described according to its relative position in the pathogenesis of an overall impairment; for example, a primary gland failure is caused by deterioration of the gland itself, whereas a secondary failure is the inefficiency of a gland due to disruption of a previous step of an axis, e.g. neural stimulus or a chemical mediator.

The 20th century saw great technological leaps bringing with them a much better understanding of the human body in both healthy function and disease, as well as understanding of the aetiology and pathogenesis of most of the worlds diseases, which saw many deadly ailments eradicated altogether while others became curable or at least more manageable.

At the smallest level, physicists such as Albert Einstein formulated theories (subsequently backed up by evidence) which greatly improved our knowledge of the atomic and sub-atomic worlds, leading to fantastic progression in the understanding of human biochemistry (White and Gribbin, 1994). This new chemical and mathematical knowledge coupled with huge strides in technology such as development of highly sensitive electrodes have yielded comprehensive knowledge of the cardiovascular system (Granger, 1998). The understanding of the human brain and its associated neural pathways throughout the body grew vastly during the 20th century following the advent of the electroencephalogram (EEG) which brought about drug treatments for previously fatal disorders such as polio and epilepsy (Swift, 2000). These and all other drug treatments evolved throughout the 1900s from vaguely understood extracts and potions to the current competitive, highly researched, proven remedies we have today (Heath and Colburn, 2000). Advances in assessment and understanding of homeostatic mechanisms led to vastly improved patient health and the eradication of various diseases such as cholera (Savarino, 2002). Knowledge of the nature and causes of cancer has hugely developed, with treatments, and possible cures and vaccines emerging, as well as cancer surgery progressing from the often indiscriminate mutilation of times past (Fisher, 2008). In fact, all surgery has been enormously enhanced to the kinds of intricate, technologically advanced procedures commonplace today. As previously mentioned, technological advancement has improved all aspects of medicine, from the imaging systems needed for diagnosis to lifesaving equipment that is now attributed to massive reductions in deaths from road traffic accidents (Dobson, 2003). Far greater knowledge of genetics has lead to the unravelling of the human genome and the pinpointing of many defects which may, through controversial genetic engineering, lead to the curing of many diseases. Stem cell technology could potentially bring about advances in cancer treatments (Dick, 2008). All of this medical knowledge is now widely available due to organisations like the NHS. Another area that has experienced terrific breakthroughs is endocrinology. We now understand the complex array of effects of hormones on their effected organs and tissues, as well as how the various organs of the endocrine system interact to produce changes in bodily functions. In a complex system such as this there are many ways for disruption to occur with devastating effects, thankfully we now know a lot about these disruptions, how they occur, can be prevented and managed or even cured. One important axis in the endocrine system is the hypothalamus-pituitary-adrenal (HPA) axis (below).


The hormones secreted by the adrenal cortex are steroid hormones synthesised from cholesterol, and are broken down as follows- mineralocorticoids (e.g. aldosterone) released from the zona glomerulosa (outer layer), glucocorticoids (e.g. cortisol) released from the zona fasciculata (middle layer), and weak androgens (testosterone, it's metabolites and precursors, and oestrogen precursors) released from the zona reticularis (deepest layer) (Sherwood, 1997).

The main glucocorticoid, cortisol, is an important hormone in stress response and metabolism, and its basic release axis is outlined in figure 1 (above).

Aldosterone, the primary mineralocorticoid, is responsible for the retention of ions and water in the kidney in response to a drop in blood pressure, is a factor in the renin-angiotensin-aldosterone axis, therefore is a major factor in blood pressure and electrolyte homeostasis in healthy function.

The adrenal cortex also produces and releases androgens, hormones important for sexual characteristics, as well as metabolism, body composition amongst other functions.

Addisons disease, named after, and by, Thomas Addison in 1855 (Howlett, 2012) could be more scientifically called primary hypoadrenalism, and is characterised by reduced functioning or complete shutdown of the adrenal cortex, often also with atrophy of the tissue. There are many causes and a variety of different ways for Addisons disease to manifest itself, and due to the complex nature of the adrenal cortex and its associated chemical pathways, disruption to many important mechanisms within the body ensues and sudden death may occur. Sadly, major symptoms often do not show until the adrenal cortex is 80-90% destroyed (Alevretis et al, 2003).

JFK famously suffered from Addisons
JFK famously suffered from Addisons | Source


There are many aetiologies associated with Addisons disease (AD), ranging from fungal infections to auto-immune disorders to metabolic disturbances. The main causes are investigated below-

  • Auto-immune adrenalitis accounts for approximately 70% of all AD cases and is elicited in infants by an autosomal recessive genetic defect of a zinc finger protein causing autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) which features recurring yeast infection and affects the adrenal and parathyroid glands as well as many other tissues (Lavin, 2002).

◦ A more common, generally adult onset cause of auto-immune adrenalitis, is type 2 polyglandular auto-immune syndrome. This polygenic syndrome which also affects many glands and other tissues, manifests as AD in 40% of cases and affects many more females than males (~3:1) (Kahaly, 2009). This AD manifestation is shown to be preceded by type 1 diabetes mellitus in the majority of cases (Papadopoulos and Hallengren, 1990). Studies have shown that lifestyle and environmental factors affect the way this syndrome progresses, as some identical twins have been found to present at different stages (Kahaly, 2009).

▪ Other more common autoimmune disorders such as coeliac disease can lead to more serious autoimmune disorders like AD, therefore it is important that these diseases are monitored and managed closely (Collin et al, 2002).

▪ Markers of auto-immune adrenalitis are autoantibodies (Abs) attacking the bodies proteins, such as adreno-cortical Abs (ACA) and Abs attacking the steroid 21-OH (steroid 21-OH Abs) (Betterle et al, 2002).

  • Infectious diseases can cause AD (see figure 2, overleaf). Presently, tuberculosis (TB) is responsible for around 5% of all cases in Western civilisation, which is a great improvement as TB was the primary cause a hundred years ago (Lavin, 2002). Adrenal TB causes hypoadrenalism by the bilateral calcification of the adrenal glands (Alevretis et al, 2003). Many other infectious diseases can, however lead to AD.

◦ Bacterial infections, such as meningococcal diseases, syphilis, and infection with bacteria such as the Streptococcus strains can infest the adrenal glands, causing necrosis of the tissue (Alevretis et al, 2003).

◦ Most fungal diseases can cause AD. Histoplasmosis and blastomycosis are amongst the most common causes (Lavin, 2002). Many others fungi, such as Cryptococcus neoformans, found in pigeon droppings, are also instigated (Alevretis et al, 2003). Most fungal infections present as swelling of the adrenal glands.

◦ Parasitic infections, such as toxoplasmosis can also lead to AD (Alevretis et al, 2003).

◦ All of the above infectious diseases can lead to sarcoidosis, a build up of granulomas on the adrenal glands, nodules of macrophages attempting to 'wall off' infectious material.

◦ Environmental factors play a large role in the development of AD from infectious diseases as these diseases are much more prevalent in poorer, undeveloped countries, as well as in the wilderness areas of the world such as jungles.

  • Viral infections that compromise immune function, specifically HIV/AIDS can cause hypoadrenalism both indirectly by reducing immune function and allowing infection of the gland, and directly by causing necrosis of the tissue (Lavin, 2002). A common cause of adrenal failure in AIDS carriers is infection with the cytomegalovirus (human herpesvirus-5), a virus generally unnoticed by healthy individuals, but devastating to immuno-suppressed individuals (Alevretis et al, 2003). With regards to AIDS, lifestyle factors may play a part as infection is commonly due to unprotected sex and illegal drug use.

  • Bilateral adrenal haemorrhage is extremely rare in healthy individuals, but is seen in frail patients undergoing intense drug therapies, such as in conjunction with anticoagulant use, and particularly when under high stress when massively increased ACTH levels place huge pressure on the vascular network surrounding the adrenal glands, especially the single adrenal vein (Lavin, 2002).

◦ Antiphospholipid antibody syndrome, or Hughes syndrome is another cause of adrenal haemorrhage as it causes blood coagulation in the small blood vessels which then rupture under pressure (Lim, 2009).

  • Adrenoleukodystrophy and the slightly milder adrenomyeloneuropathy are autosomal, x-linked disorders affecting children, and are primarily associated with progressive defects in the myelin sheaths surrounding neurons causing decreasing neural function (Lavin, 2002). An irregularity with a peroxisomal membrane protein involved in beta-oxidation, leading to an accumulation of very long-chain fatty acids (VLCFA) is thought to be the underlying cause of these conditions (Forss-Petter et al, 1997). The adrenal glands are heavily affected due to their extensive contact with lipids in the production of their associated steroid hormones, and it is thought that the VLCFA's compete for ACTH binding sites (Lavin, 2002).
  • Lymphoma (cancer of lymph tissues) is another cause of AD and can affect one, or both adrenal glands (Mantzios et al, 2003). These tumours generally cause noticeable enlargement of the adrenal glands, but not in all cases, and can bring about AD in a variety of ways, such as by obstructing local blood vessels or simply by invading the tissues (Park et al, 2007).
  • Primary cancer of the adrenal gland does occur, but far more commonly these cancers are caused by cells that have metastasized from other cancers, nearby renal malignancies being a major cause, breast and lung cancers also common causes (54% and 44% respectively of these cancers presenting secondaries metastasize to the adrenal glands) (Lavin, 2002). Adrenal metastases only present symptoms of AD in 4% of cases of fatalities from the primary cancers and by this point the primary tumours are generally well developed so the secondaries are of little importance (Lam and Lo, 2002). It is almost unheard of for a patient to die as a direct cause of a secondary adrenal cancer.
  • Some other rare causes of AD are-

◦ Genetic triple A syndrome (Allgrove syndrome), where a gene defect on chromosome 12q13 leads to adrenal insufficiency (one of the A's) by causing ACTH resistance (Menon et al, 2008).

◦ POEMS syndrome (Takatsuki disease) is a very rare disorder affecting many parts of the body in different ways. There is usually degeneration of neuronal myelin sheaths as in adrenoleukodystrophy (previous page) and adrenal insufficiency is reported in approximately 25% of cases (Dispenzieri et al, 2002).

◦ Abnormal distribution of amyloid proteins in the kidney, known as renal amyloidosis, can lead to adrenal insufficiency secondary to complete renal failure (Harvey et al, 1995).

◦ Some extremely rare gene mutations exist that affect or even prevent the binding, action and activation of pre-hormones and messengers such as ACTH (Lavin, 2002).



Although there are many, widely varying aetiologies for AD, in most cases the disease progresses through similar symptoms, the largest variable being the speed of progression. The outward signs of the sufferer may vary comprehensively however, due to their particular underlying cause of AD affecting other organs and bodily functions.

Symptoms of AD include: lightheadedness (especially upon standing), fatigue, weakness, fever, anxiety, nausea, stomach complaints, headache, sweating, joint and muscle pain, changes in mood (especially increased anxiety), darkening of the skin, weight loss, and a craving for salty foods (Howlett, 2012). The reason for all of the above symptoms becomes apparent when the mechanisms disrupted by AD are fully understood.

The primary mineralocorticoid (mineral-cortex-steroid) aldosterone is responsible for the homeostasis of the principal electrolytes within the body, mainly sodium and potassium, therefore increases blood volume and maintains proper cellular function. Aldosterone is mainly stimulated through the renin-angiotensin-aldosterone axis (RAAA(figure 3)), which is triggered by a fall in blood pressure/volume detected by the juxtaglomerular apparatus in the kidney, which secretes renin into the blood, which converts inactive angiotensinogen into angiotensin I, which is then converted to angiotensin II, which stimulates the adrenal cortex to produce and secrete aldosterone (Sherwood, 1997). Angiotensin II causes water retention by stimulating the thirst reflex and anti-diuretic hormone (ADH) secretion, thereby diluting the plasma and reducing osmolarity, the actions of aldosterone are therefore essential as only a small change in osmolarity and electrolyte balance can have devastating effects on the body.

There are other ways in which aldosterone secretion is stimulated, such as high plasma concentrations of ACTH, plasma acidity and by neural stimulation from stretch receptors in the heart. These provide only minor stimulus compared to the RAAA, the only other factor which rivals this axis is stimulus from hyperkalaemia, a direct result of hypoaldosteronism, so a vicious circle is established (Sherwood, 1997).

Due to the absence of aldosterone (the most dangerous aspect of AD), AD sufferers experience huge losses of sodium in their urine, which explains the craving for salty foods, lightheadedness, fatigue and nausea (electrolyte imbalance), muscle pain (cramping), and excess sweating and diarrhoea (as the body attempts to restore plasma osmolarity). These sodium losses, together with the excess fluid loss cause a drop in blood volume, therefore hypotension, again explaining the lightheadedness and nausea. If this hypoaldosteronism continues untreated the body will go into shock and, after a last minute effort by the body to restore harmony, death is sure to follow (Evans and Greenberg, 2005). Medical signs of hypoaldosteronism also include elevated levels of ADH and angiotensin II and its metabolites.

The secretion of the primary glucocorticoid, cortisol, is directly stimulated by ACTH through the HPA axis (see figure 1). The main functions of cortisol are stress management (physical, chemical or psychological), inhibiting inflammation, and the control of macronutrient metabolism, particularly carbohydrates (raising blood sugar) (Sherwood, 1997). Therefore the principal stimuli of this particular branch of the HPA axis are stress, inflammation and reduced blood sugars (or amino and fatty acids).

Hypocortisolism causes a depleted response to stress and inflammation, explaining the symptoms of fever, pain and anxiety, and perhaps most importantly, causes metabolic disturbances, especially hypoglycaemia, explaining lightheadedness and headaches (the brain can only use glucose for fuel), as well as fatigue and weakness. An important medical sign of hypocortisolism is highly elevated blood levels of ACTH as cortisol is not present to negatively feedback on the hypothalamus and pituitary gland. An outward sign of excess ACTH is hyperpigmentation of the skin as the pre-cursor of ACTH is also a pre-cursor for melanocyte stimulation (Lavin, 2002). A decrease in cortisol levels also leads to widespread vasodilation, further enhancing the patients hypotension (Sherwood, 1997).

AD also shuts down production of androgens in the adrenal cortex. This would have little effect in a healthy person as this is a secondary site for androgen secretion, it could however, affect children or a person whose primary sites were insufficient or had been removed (Sherwood, 1997). The effects, if any, of hypo-secretion of adrenal androgens would include weakness and weight loss.

Many of the symptoms outlined above may be masked in patients undertaking steroid treatments for other ailments.

Many other factors can influence the pathogenesis of AD and the severity of the symptoms of the disease. An example of this is pregnancy. During certain periods of pregnancy the bodies need for cortisol increases, enhancing the severity of the symptoms of AD, particularly if the disease is undetected or not being treated at the time (Bjornsdottir et al, 2010). The risk of malformations of the baby also increase with AD (Bjornsdottir et al, 2010). As well as the electrolyte disturbances detailed above, extremely low levels of phosphate may also occur, leading to confusion, seizures and eventually, respiratory failure (Meisterling et al, 2011). Lifestyle factors may be decisive in the development of hypophosphataemia as low dietary intakes and high phosphate turnover, for instance from high activity levels, would aggravate this condition. The autoantibodies responsible for autoimmune AD may also attack other steroid producing tissues within the body, for example the ovaries (Hoek et al, 1997). Mild forms of AD have been documented to present as periodic fever syndrome, a chronic condition where the sufferer experiences recurring bouts of fever that may be misdiagnosed as fatigue, anaemia and many other ailments (Sharretts and Nieman, 2011).

Untreated or under-managed AD will eventually lead to a condition known as Addisonian crisis, an extremely serious condition requiring immediate emergency treatment to provide any chance of avoiding death. The symptoms of Addisonian crisis are: severe vomiting, diarrhoea, hypotension, hypoglycaemia, hyperkalaemia and hyponatraemia with severe lethargy, delirium and fever, leading to convulsions, unconsciousness and eventually death (Lavin, 2002). An Addisonian crisis can also be elicited in AD sufferers by many independent conditions, such as bouts of asthma attacks, diabetic problems and infections, in fact studies have shown that approximately 8% of AD sufferers will require hospital treatment for Addisonian crises annually (White and Arlt, 2010). AD sufferers undergoing stressful operations are also at highly elevated risk of developing a crisis situation (D'Silva et al, 2012). Some of the causes of AD discussed above can cause immediate crisis without any prior symptoms, these include adrenal haemorrhage and massive infiltration by infectious disease.

Hyperpigmentation caused by Addisons
Hyperpigmentation caused by Addisons | Source


There are various methods of treatment available for AD sufferers, the exact course chosen for a particular case depending on the aetiology and severity of their condition.

There is currently no known cure for genetically inherited causes of AD, such as APECED and adrenoleukodystrophy. Inactivation of the primary gene responsible for adrenoleukodystrophy in mice have shown improvements but not total irradication of the disease as other genes or factors are suspected to be involved (Forss-Petter et al, 1997). The current treatment available is steroid hormone replacement therapy, which enables patients to lead a reasonably normal life but lacks the fine control or diurnal rhythm of the bodies tight homeostatic control (Lavin, 2002).

Drastic medical and surgical intervention is often needed where haemorrhage and/or cancer is present. Chemotherapy may be used to control tumours and adrenalectomy (removal of glands) is often necessary in extreme cases. Hormone replacement must be administered following these procedures. There are some effective drugs available to sufferers of lymphoma, for example Retuximab, an antibody cloned in laboratories which directly attacks the tumours (Cancer Research UK, 2011).

Bacterial infections can be treated with antibiotics before any damage and lasting effects can be evaluated and further addressed. Powerful drug treatments are often the only recourse available to doctors in cases of tuberculosis, viral and fungal invasions (Alevretis et al, 2003). Some drug therapies for fungal infections have been shown to worsen AD, a potentially dangerous situation for the undiagnosed sufferer (Lavin, 2002).

A few dietary modifications have been suggested to aid in the management of AD. The most well documented of these is Lorenzo's oil, a mixture of two specific long chain fatty acids purported to slow the progress of adrenoleukodystrophy. There are mixed opinions in the scientific community about this treatment, there are parties who would recommend its use in certain cases (Moser et al, 2005) and others who have found little or no evidence to back up the claims and would prefer to support the scientifically proven, albeit more rigorous and 'less natural' therapies available (Van Geel et al, 1999). Another dietary intervention which has received some evidential support in recent times is the consumption of grapefruit and licorice to increase the availability of administered cortisol therapy (Methlie et al, 2011).


In conclusion, AD is a thankfully rare, but devastating disease which often only fully presents itself when any chance of full recovery is gone. The complex array of aetiologies associated with AD means that symptoms are often confused with, and masked by signs of other ailments affecting the patient. Routine testing of the population for markers of AD are certainly beyond the scope of any publicly funded healthcare system. In terms of the cure of AD, advances in genetic research and immunological understanding must surely pave the way for increasingly effective management of the most common cause of the disease, auto-immune disorders.


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