Addison's Disease and Adrenal Insufficiency - Essay Example

?Addison’s Disease-General Overview Addison’s disease is an adrenal insufficiency disorder that arises because of autoimmunity, diseases such as HIV and tuberculosis, or X-linked adrenoleukodystrophy. It may occur in isolation or in combination with other autoimmune diseases such as type 1 diabetes. Autoimmunity remains the chief cause of Addison’s disease in Europe and in Africa, although the incidence rates in Africa are comparatively low. The key immunological finding in most patients is the presence of autoantibodies against cytochrome P450 21-hydroxylase, an essential enzyme in the biosynthesis of adrenal steroid hormones. Inadequate amounts of adrenal hormones present symptoms such as hypoglycemia, fatigue, vomiting, and hyperpigmentation among many others. A careful examination of morning cortisol levels and amounts of ACH aid in giving correct diagnosis for patients with Addison’s disease. The only treatment available is replacement therapy using synthetic glucocorticoids and mineralocorticoids. However, it is vital that diagnosis is made early enough to ensure that the patients start treatment on time and enjoy productive lives. Key Words: Addison’s disease; Adrenal insufficiency; Autoimmunity Introduction Addison’s disease is an endocrine and immunological disorder that leads to adrenal insufficiency. The pituitary gland secretes excess adrenocorticotropic hormone to make up for the reduced amount of cortisol in the adrenal glands (Burk et al. 215). Autoimmune Addison’s disease occurs due to adrenal inadequacy because of immune mediated destruction of the adrenal cortex (Rottembourg et al. 309). In 1849, Dr. Addison illustrated a form of anemia that had been overlooked. This ailment was common in men between the ages of 20 and 60. It was characterized by a slow onset and took several weeks or even months to display alarming symptoms such as immense fatigue, paleness, and mental and physical incapacitation (Bishop 35). A postmortem of three cases revealed a diseased condition of the suprarenal capsules, which Dr. Addison believed was not a happenstance. He, therefore, decided that the suprarenal capsules were indirectly or indirectly involved in the events that led to the diseased condition. In 1855, Dr. Addison published a monograph addressing the consequences of disease on the suprarenal capsules. It sought to establish the actual functions and impact of these cells. The monograph associated the similarities of the renal suprarenal capsules with the spleen, thyroid body, and thymus to the embellishment of blood (Bishop 36). He further described the progression and key symptoms of the problem and explains that all cases defied curative endeavors and ended lethally. It is worth noting that during that time the functions of the supra-renal capsules were unknown. Later on in 1856, Trousseau called the condition “La Maladie d’ Addison” (Bishop 37). Charles Edouard Brown-Sequard collected a number of rabbits, cats, and dogs and deprived them of their adrenals. He thought that if the animals did then they would have died because of Addison’s disease. A pressor substance was discovered in the adrenal medulla in 1894 after which Takamine and Aldrich separately isolated the crystalline form of adrenaline in 1091. Having been synthesized in 1904, adrenaline became the first hormone to be isolated chemically, characterized, and synthesized (Bishop 38). It was then discovered that cortical extracts contained substances that preserved life. The clinical syndrome as described by Dr. Addison was later called Addison’s disease following his relation of adrenal insufficiency to the symptoms. Addison’s disease is prevalent in Western countries compared to African countries as established by Ross et al. during a cohort study of South Africans (292). Etiology There are several causes of Addison’s disease such as marred steroidogenesis, adrenal dysgenesis, and diseases that lead to the destruction of the adrenal cells (Burk et al. 215). Autoimmune destruction of the adrenal cells remains the main cause of Addison’s disease currently. Autoimmune Addison’s disease occurs when immune cells turn against the supra-renal cells. This is an autoimmune disease where the body fails to distinguish its own cells as self and begins destroying them. In this case, the adrenal cells are recognized as foreign and destroyed by the immune cells, a phenomenon that leads to renal insufficiency hence Addison’s disease. Addison’s disease is among the most prevalent autoimmune diseases with an incident rate of 18 out of 100,000 people in the United Kingdom, Italy, and Norway (Cooper, Bynum & Somers 198). The body produces autoantibodies against the enzyme 21-hydroxylase. According to Cooper, Bynum and Somers 21-hydroxylase is a critical enzyme in the synthesis of steroid hormones such as cortisol and aldosterone (198). The expression of this enzyme in humans occurs primarily in the endocrine cells found in the adrenal cortex. According to Bratland et al., the presence of antibodies against 21-hydroxylase is not sufficient to cause the condition (58). However, the T-cell mediated immunity because of the antibodies is the main cause of the disease. The further support this with an observation that the maternal transfer of theses autoantibodies to a fetus does not cause renal insufficiency in the fetus. Addison’s disease occurs “in isolation (IAD) or as one component of an autoimmune polyendocrine syndrome (APS 1 or APS 2)” (Rottembourg et al. 309). Non-endocrine ailments such as vitiligo and celiac disease can also cause AAD (Bratland & Husebye181). AAD is commonly found in APS (autoimmune polyendocrine syndrome type 1), in association with parathyroidism and mucocutaneous candidiasis together with other endocrine and nonendocrine symptoms (Bratland & Husebye 181). The hallmark of this condition is the existence of autoantibodies targeted against 21-hydroxylase, a steroidogenic enzyme that is expressed in the adrenal cortex. Tuberculous adrenalitis also causes AD and remains the key cause of Ad in developing countries (Bratland & Husebye 181). The instigation and maintenance mechanisms of the condition, however, remain unknown. The initiation of adrenal autoimmunity requires a collection of endogenous, environmental, and genetic factors. Target cells in AAD also play a significant role in their destruction by the immune system. The normal adrenal cortex is highly vascularized and interrelates with the circulating lymphocytes. The adrenocortical production of mineralocorticoids and glucocorticoids is controlled by cytokines and chemokines secreted by the immune cells in the circulation. The hormone-secreting cells of the adrenal cortex also produce chemokines and cytokines such as IL-1, IL-6, IL-18, interferon inducible protein 10, and tumor necrosis factor ? (Bratland & Husebye 182). The endocrine cells of the adrenal cortex also produce toll-like receptors (TLRs), noteworthy constituents of the innate immune system. TLRs play a significant role in the endocrine rejoinders to septicemia and infections. It is proposed that the expression of these vastly immunologically pertinent molecules plays a role in the pathogenesis of AAD. X-linked adrenoleukodystrophy (X-ALD) is a peroxisomal malady that affects the adrenal cortex, testicular function and the central nervous system (Polgreen et al. 1049). Adrenal insufficiency is prevalent in boys with X-ALD and paves the way for explicit neurological association especially in young subjects. This condition is frequently not diagnosed in boys with X-ALD. This implies that suffering from X-ALD also causes adrenal insufficiency, and that X-ALD is the main cause of Ad in young boys (Horn et al. 3). Certain infections can put people at risk of developing adrenal insufficiency. These ailments include HIV, tuberculosis, and fungal infections (Howlet & Pearce 29). An obvious decline in the requirement of insulin during established diabetes can indicate that the patient is developing hypoadrenalism. Clinical Characteristics Glucocorticoids secreted by the adrenal cortex have a gluconeogenic effect through various pathways. One of the pathways involves the conversion of oxaloacetate into phosphopyruvate. This increases the activity of the liver glucose 6-phosphatase that liberates additional glucose into the circulation. Consequently, hypoglycemia is a key trait in AD due to the lack of these glucocorticoids. Adrenal insufficiency can also lead to myocardial dysfunction due to low serum phosphorus concentrations. Other symptoms of Addison’s disease include overpowering exhaustion, loss of appetite, nausea, and dizziness experienced during standing. There is a lot of weakness in the muscles, muscle cramps, abdominal and joint aches (Howlet & Pearce 29). The patient also feels thirsty frequently and prefers the intake of salty foods. Other crucial signs include low blood pressure, a deepening skin coloration, and postural hypertension. Severe forms of the disease may also lead to shock incidences. Some patients report ‘flu-like symptoms’ and may think that they have a bout of flu. Dermatological problems such as the loss of ambisexual hair in women who are past their puberty may also be present. The deep skin coloration (hyperpigmentation) arises because of the high amounts of proopiomelanocortin produced by the pituitary. Proopiomelanocortin is split to form ACTH and melanocyte stimulating hormone (Burk et al. 217). Melanocyte stimulating hormone is responsible for overproduction of melanin cells hence the hyperpigmentation. It is pronounced in the gingival regions, face and neck, and along the mucosal surface of the lower lip (Burk et al. 216). Figure 1: Hyperpigmentation along the mucosal surface of the lower lip (Burk et al. 216). The initial symptoms of Addison’s disease resemble those of type 1 diabetes mellitus; however, in adrenal insufficiency the blood glucose is usually low. The prevalent symptoms exhibited during primary autoimmune adrenal insufficiency are effects of the deficiency of mineralocorticoids. The increasing skin pigmentation is usually because of high ACTH levels (in response to low amounts of circulating the disseminating glucocorticoids). Figure 2: Hyperpigmentation in the gingival region (Burk et al. 216). Secondary stages of autoimmune adrenal insufficiency do not show skin depigmentation. However, the skin takes on an “alabaster-like pallor” (Howlet & Pearce 29). In more than 40 % of the patients, hypothyroidism occurs. High levels of the thyroid stimulating hormone (TSH) are a sign of hypoadrenalism, but without other feature of hypothyroidism. A study by Meisterling, Chawla, and Seneff reveal a rare case of hypoglycemia owing to Addison’s disease. This isolated case leads to hypophosphatemic respiratory failure (319). Cartilage calcification, fibrosis, vitiligo, chronic mucocutaneous candidiasis, and the mentioned dermatological ailments are also crucial symptoms that aid a physician in making the correct diagnosis (Burk et al. 217). The clinical manifestations of Addison’s disease are the same in both African and European patients as is shown by a study on South African patients (Ross & Levitt 3). Immunological Findings Studies reveal that interferon gamma secretion of T-cells occurs in the presence of 21-hydroxylase enzyme in patients with AD (Rottembourg et al. 309). In addition, APS 2 patients display faults in the functioning of T-cells. These defects manifest as the marred expression of caspase 3 that participates in the apoptosis of T cells and the destroyed suppressive roles of CD4+ and CD25+. However, it remains unclear whether 21-hydroxylase participates in the pathogenesis of human autoimmune adrenal failure (Rottembourg et al. 310). This is due to lack of suitable animal models for the experiments. Rottembourg and colleagues seek to establish whether CD8 T cells go for 21-hydroxylase antigenic determinants in autoimmune Addison’s disease. They do so by establishing the precise T-cell rejoinders to 21-hydroxylase in the hope that such a revelation paves way for further inquiry on the pathogenic functions of these T cells. They use patients with a clinical diagnosis of AD (with antibodies against 21-hydroxylase) as the test subjects and controls including 8 healthy adult volunteers and 9 diabetic children without 21-hydroxylase enzymes. They realize that patients with AD show T cell reactivity to 21-hydroxylase peptides. The magnitude of IFN? responses was considerably higher (above 50 spot forming cells per 106 lymphocytes) in patients with adrenal disease, whereas the response was low (below 50 spot forming cells per 106 lymphocytes) for the controls. They also realize that the responses are more pronounced in patients with a short duration (less than 5 years) after diagnosis. A further test shows that CD8+ T cells are the cells that cause the specific reactions with 21-hydroxylase. They conclude that 21 hydroxylase is the key T cell autoantigen in AD regardless of the clinical context of the ailment (Rottembourg et al. 312). It is known that HLA class I molecules attach and present peptides of between 8 and 11 amino acid residues. However, the study detects IFN? rejoinders brought out by CD8 T cells using 20mer peptides (Rottembourg et al. 312). This shows that the ELISPOT assay used had cross presentation machinery. Therefore, the 8 to 11 amino acid residues necessary for the reaction are present in the 21-hydroxylase 20mer peptide that was used. A separate study by Bratland et al. proves that 21-hydroxylase is the autoantigen in AAD by immunizing mice with purified 21-hydroxylase and observing the immune responses (in the mice lymph nodes) in the form of the proliferation of interferon gamma (63). Ovalbumin is utilized as the negative control. This experiment shows that amount of IFN? increases as the concentration of injected 21-hydroxylase increases. These findings are clearly shown in figure 3 below. Figure 3: Lymph node cell responses to 21-hydroxylase (Bratland et al. 63). Other studies show that the autoantibodies against 21-hydroxylase class switch to IgG1 subtype, a mechanism that implies a CD4+ T cell rejoinder against the protein (Bratland et al.59). However, the actual mechanisms of the reaction are still unknown. In a separate study, Bratland et al. try to establish the immune responses to recombinant 21-hydroxylase in immunized SJL/J mice, AD patients, and uninfected individuals. It is shown that Sf9 cells of all the three categories of test subjects express the recombinant 21-hydroxylase in the expected proportions with fragments of 50 to 60 kDa being the most abundant. A western blot analysis of the sera using monoclonal anti-hexahistidine antibody is done against “Sf9 cell lysate (Sf9-21OH), uninfected Sf9 cell lysates (Sf9-MOCK), and MagicMark Western protein standard (M) (Bratland et al. 61). The study shows that control uninfected Sf9 cell lysates do not express immunoreactive proteins. These are summarized by figure 4 below. Figure 4: Western blot analysis of Sf9 cell lysates (Bratland et al. 62). A separate report by Ross et al. reports that adrenocortical autoantibodies are also present in patients suffering from AAD (291). However, the most prevalent autoantibodies in patients are the 21-hydroxylase autoantibodies. Histopathological Findings Careful studies of the tissues of deceased AD patients reveal a pronounced mononuclear cell infiltrate (Bratland et al. and Rottembourg et al.). In addition, the disease damages the adrenocortical parenchyma. Certain HLA haplotypes especially DR3-DQ2, and DR4-DQ8 are associated with APS 2 and IAD. These allelic combinations are also known to prompt other T-cell mediated autoimmune ailments such as celiac disease and type 1 diabetes (Rottembourg et al. 310). The progression of the condition gradually damages all the layers of the adrenal cortex, which produce hormones. Fibrous tissue gradually substitutes the destroyed cells. Clinical symptoms begin manifesting after the destruction of about 90% of the adrenal cortex cells (Bratland & Husebye 181). The active stage of the condition entails high expression of MHC class II molecules (Major histocompatibility complex) by the adrenocortical cells. Most of the cells become positive to MHC class II because of excessive contact with interferon gamma produced by the activated T cells. Figure 5: Immunohistopathogenesis of autoimmune Addison’s disease (Bratland & Husebye 185). Genetic factors Genetic factors are the best-depicted traits for AAD, most of which encode proteins that take part in the presentation of antigens and activation of T cells. The enzyme 21-hydroxylase is a microsomal cytochrome P450 enzyme containing heme. It is encoded for by the CYP21A2 gene (Bratland et al. 58). A mutation in the IRE gene causes APS 1. Some studies report that AD has some association with the HLA A1-B8-DR3 ancestral haplotype (Rottembourg et al. 309). Class II HLA alleles in the MHC complex are mainly associated with a genetic predisposition to AAD (Bratland & Husebye 181). The presence of HLA-DRB1*03-DQA1*0501-DQB1*0201(DR3/DQ2) and DRB1*0404-DQA1*0301-DQB1*0302 (DR4.4/DQ8) haplotypes highly escalates he risk of developing AAD (Bratland & Husebye 181). The presence of DR4.4 initiates proper presentation of the 21-hydroxylase peptide to autoreactive T cells. It is also known that about a fifth of all AAD patients carry the DR4.4 allele, signifying that other alleles are also significant in the disease. Recent studies reveal that the preserved DR3-B8 HLA haplotype plays a prominent role in increasing the risk of AAD in multiplex families. A recent fascinating observation is that the HLA class I allele B8 is highly expressed autonomously of DR3 in AAD patients, an occurrence that is in line with the discovery of a B8-restricted T cell antigenic determinant in 21-hydroxylase (Bratland & Husebye 181). In addition, there is a relation “between AAD and allele 5.1 of the non-classical MHC molecule MHC class I chain-related A (MIC-A)” (Bratland & Husebye 181). It is proposed that homozygosity for the 5.1 allele of MIC-A in the presence of the high-risk HLA genotype can classify individuals with an extremely high risk of developing explicit AAD. The table below gives Autoimmune Addison’s disease non-MHC disease susceptibility genes. Susceptibility gene Protein function References CTLA4 A key negative regulator in adaptive immunity Blomhoff et al. (2004) CIITA The MHC class II transactivator (MHC2TA), which regulates the expression of MHC class II molecules Ghaderi et al. (2006) and Skinningsrud et al. (2008b) PTPN22 The tyrosine-protein phosphatase non-receptor type 22, involved in regulation of T cell receptor signaling Roycroft et al. (2009) and Skinningsrud et al. (2008a) PD-L1 The programmed death ligand 1, ligand of the PD-1 receptor, an inhibitory molecule expressed on activated T cells Mitchell et al. (2009) Figure 6: Autoimmune Addison’s disease non-MHC disease susceptibility genes (Bratland & Husebye 182). Several genes beyond the MHC complex increase the genetic susceptibility to the disease. These genes encode proteins that participate in activation and control of T cells that are antigen specific, and play a significant role in other autoimmune diseases. According to Bratland and Husebye, vitamin D plays an essential immunoregulatory role such as the down regulation of T cell production and secretion of cytokines (182). In addition, vitamin D also impedes the maturation and instigation of macrophages and dendritic cells. In conclusion, polymorphisms in the gene that codes for the NACHT leucine-rich-repeat protein 1(NALP1) increases genetic susceptibility to AAD (Bratland & Husebye 182). This is because the NALP proteins participate in inflammatory rejoinders mediated by cytokines in family1 (interleukin-1, interleukin-18, and interleukin-33). It is also known that African patients with autoimmune Addison’s disease have a distinct profile of antibodies compared to the European patients (Ross et al. 292). This is probably due to the slight differences in the genetic constitution of Africans and Europeans. However, autoimmunity is the main etiological factor of Addison’s disease in Africans and is associated with the HLA DQB1*0201 gene. Diagnostic Criteria According to Rottembourg et al., the main diagnostic feature of Addison’s disease is the presence of autoantibodies against the enzyme 21-hydroxylase (309). Patients who are at risk of getting the disease also have these antibodies before the presentation of this disease. More often than not, they are usually relatives of patients suffering from Addison’s disease or some other form of autoimmune disease. These antibodies are the key indicators of T cell arbitrated damage of the adrenal cortex. However, when a patient first gets to a health facility, there are certain diagnostic criteria that a general practitioner uses to establish the possibility of Addison’s disease. These include measurement of the patient’s blood pressure while sitting and standing. The rationale behind this is that postural hypertension causes a 20-point fall in blood pressure on standing (Howlet & Pearce 29). The oral mucosa ought to be scrutinized for patchy hyperpigmentation especially in areas that experience a lot of friction. A general practitioner also ought to find out whether the patient suffers from fatigue and finds it hard to perform tasks such as climbing stairs of getting up from a sitting posture. A laboratory test to determine the electrolyte levels, blood glucose, and 9 am cortisol are also mandatory. The diagnosis is likely if the 9 am cortisol level is less than 100 nmol/l unless the patient is taking inhaled or oral steroids. However, a brief Synacthen or ACTH stimulation test is essential to give proper diagnosis if the cortisol values are between 100 nmol/l and 400 nmol/l (Howlet & Pearce 29). Whenever in doubt it is recommended that the general practitioner make a referral of the patient to an endocrinology specialist for further tests. These tests include “plasma ACTH, plasma DHEA-S, thyroid function tests, and organ specific antibodies” (Howlet & Pearce 29). To rule out the disease, the ACTH levels ought to be between 5–27 pg ?mL (Burk et al. 216). Primary adrenal insufficiency may happen without the occurrence of diffuse hyperpigmentation. For this reason, a doctor using hyperpigmentation to make a diagnosis may delay in giving the correct diagnosis. Emergent Therapies A replacement therapy is the only available treatment option in Addison’s disease. This involves the regular supplementation of glucocorticoids and mineralocorticoids such as hydrocortisone. However, this therapy does not reinstate the physiological hormone concentrations and biorhythm (Bratland and Husebye 180). The best possible therapy is the detection and targeted prevention of AAD. Unfortunately, it is not possible to attain this due to inadequate comprehension of the pathogenic occurrences that lead to immune-mediated adrenocortical breakdown. Impediments in getting adrenocortical tissue from recently diagnosed patients further prevent the comprehensive studies on the According to Polgreen et al. the early diagnosis of related ailments such as X-ALD can go a long way in preventing the fatal stages of Addison’s disease (1049). Emergency cases of hypoglycemia due to AD are usually treated with immediate administration of dextrose to restore the blood sugar level before further treatment can be administered. Meisterling, Chawla, and Seneff suggest close monitoring of AD patients administered with glucocorticoids 48 during the initial 48 hours especially when the patient receives dextrose supplementation for hypoglycemia (320). This is beneficial in preventing myocardial dysfunction. Dexamethasone and fludrocortisone therapies are some of the synthetic hormones that are uses in the replacement therapy (Burk et al. 217). The main goal when administering these therapies is to give the lowest effective dose to match the natural concentrations of the hormones as much as possible. Many studies reveal that traditional glucocorticoid replacement dosages are usually larger than the amounts normally secreted by the adrenal glands (Bjornsdottir et al. 187). This raises concern about the long-term undesirable upshots on the bones. Pharmacological dosages of glucocorticoids administered in Cushing syndrome escalate the risks of fractures. They also influence the peak bone mass and cause the development of osteoporosis. This is particularly common in bones containing high trabecular bone content (Bjornsdottir et al. 187). Patients with AD also lack adrenal androgens, a factor that further contributes to osteoporosis. Bjornsdottir et al. show that patients with AD have higher chances of having hip fractures especially in women above the age of 50 years (193). Prognosis The prognosis of patients with Addison’s disease varies with the time between the onset of the condition and diagnosis. Sometimes it takes time before a patient is correctly diagnosed with Addison’s disease because the clinical symptoms take weeks, months, or even longer to develop (Meyer et al. 92). Most times a diagnosis is only made when a life-threatening adrenal catastrophe is reached, which may lead to premature deaths. Early diagnosis and commencement of replacement therapy is the best way to manage Addison’s disease. The replacement therapy entails a daily intake of glucocorticoids and mineralocorticoids. When proper care is taken, patients can live a healthy for 20 or more years. Therefore, the availability of synthetic glucocorticoids and mineralocorticoids has changed Addison’s disease from a potentially life-threatening illness to a manageable chronic ailment. However, the quality of life reduces drastically for most patients especially if the diagnosis is made late (Meyer et al. 93) Conclusion Addison’s disease is a potentially fatal condition if care is not taken. However, the advent of synthetic glucocorticoids and mineralocorticoids has made it manageable. Relatives of affected patients are likely to develop the disease. It is, therefore, necessary for further studies to be carried out to establish if it is possible to thwart the occurrence of the disease in people who are at risk. General practitioners need to be careful in their diagnoses to ensure that no case goes undetected to enable early commencement of treatment in the affected patients. References Bishop, P. M. F. (1949). The history of the discovery of Addison's disease. Proceedings of the royal society of medicine 43, 35-42 e1. Bjornsdottir, S., Saaf, M., Bensing, S., Kampe, O., Michaelsson, K., & Ludvigsson, J. F. (2011). Risk of hip fracture in Addison’s disease: a population-based cohort study. Journal of Internal Medicine 270,187–195. Bratland, E., Bredholt, G., Mellgren. G., Knappskog, B., Mozes, E., & Husebye E. S. (2009). The purification and application of biologically active recombinant steroid cytochrome P450 21-hydroxylase: The major autoantigen in autoimmune Addison’s disease. Journal of Autoimmunity 33, 58–67. Bratland, E. & Husebye, E. S. (2011). Cellular immunity and immunopathology in autoimmune Addison’s disease. Molecular and Cellular Endocrinology 336, 180–190. Burk, C. J., Ciocca, G., Heath, C. R., Duarte, A., Dohil, M., & Connelly, E. A. (2008). Addison’s disease, diffuse skin, and mucosal hyperpigmentation with subtle “flu-like” symptoms—a report of two cases. Pediatric Dermatology 25, 215–218, e2. Cooper, G. S., Bynum, M. L. K., & Somers, E. C. (2009). Recent insights in the epidemiology of autoimmune diseases: Improved prevalence estimates and understanding of clustering of diseases. Journal of Autoimmunity 33, 197–207. Horn, A. M., Erichsen, M. M., Wolff, A. S. B., Mansson, J., Husebye, E. S., Chantal M.E. Tallaksen, C. M. E., & Skjeldal, O. H. (2013). Screening for X-linked adrenoleukodystrophy among adult males with Addison’s disease. Blackwell Publishing, doi: 10.1111/cen.12159. Howlet, T., & Pearce, S. (2009). How not to miss Addison’s disease. Pulse 29. Meisterling L., Chawla, L. S., & Seneff, M. G. (2012). Treatment of Addison disease and subsequent hypophosphatemic respiratory failure. Journal of Intensive Care Medicine 27, 319-321 e5. Meyer, G., Hackemann, A., Penna-Martinez, M., & Badenhoop, K. (2013). What affects the quality of life in autoimmune Addison’s disease? Hormone and Metabolic Research 45, 92-95. Polgreen, L. E., Chahla, S., Miller, W., Rothman, S., Tolar, J., Kivisto, T., Nascene, D., Orchard, P. J., & Petryk, A. (2011). Early diagnosis of cerebral X-linked adrenoleukodystrophy in boys with Addison’s disease improves survival and neurological outcomes. European Journal of Pediatrics 170, 1049–1054. Rottembourg, D., Deal, C., Lambert, M., Mallone, R., Carel, J., Lacroix, A., Caillat-Zucman, S., & Deist, F. (2010). 21-Hydroxylase epitopes are targeted by CD8 T cells in autoimmune Addison’s disease. Journal of Autoimmunity 35, 309-315. Ross, I. L., Boulle, A., Soule, S., Levitt, N., Pirie, F., Karlsson, A., Mienie, J., Yang, P., Hongjie Wang, H., She, J., Winter, W., & Schatz, D. (2010). Autoimmunity predominates in a large South African cohort with Addison’s disease of mainly European descent despite longstanding disease and is associated with HLA DQB*0201. Clinical Endocrinology 73, 291–298. Ross, I. L. & Levitt, N. S. (2013). Addison’s disease symptoms – a cross sectional study in urban South Africa. Plos one 8(1): e53526. Read More