Addison Disease

Addison Disease

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Addison Diseases

Addison disease was named after the person who discovered it Dr. Thomas Addison who was British Surgeon. In 1849, he begun to look at adrenal insufficiency although endocrine function was yet to be explained. He discovered and explained the disease from autopsies that he performed on victims that had died from adrenal insufficiency. At that time there was no cure for the disease and those who suffered from it eventually succumbed as often they contracted tuberculosis as well. From then research into the disease were conducted in order to have better understanding of it including its cause by analyzing molecular basis of the disease. This paper delves into explaining the etiology of the disease including its molecular basis.

Addison’s disease is a chronic disease that results when the adrenal glands do not produce sufficient or fail to produce the hormones cortisol and aldosterone and for this reason, the disease is at times termed as chronic adrenal insufficiency or hypocortisolisms. The disease symptoms vary from one person to another. Visual development of the disease is elaborate over time and is often non-specific at first. It affects a number of individuals It affects a number of individuals worldwide and it affects both men and women worldwide (Erichsen, 2009). It is illustrated by uncontrolled weight loss, severs muscle weakness fatigue and low blood pressure, and in other cases the skin may darken. In most cases, Addison’s disease is caused by severe destruction on the adrenal cortex the outer part of the adrenal gland. The damage is often caused by the immune system. The Immune system might attack the adrenal gland causing severe damage to the adrenal cortex.

Addison’s disease is likely to occur among Caucasian European adults and has been found to occur in 140 people per million. The auto immune disease is also highly heritable when compared to other autoimmune conditions as researchers have discovered the prevalence rate of the disease to be in the ratio 160-210 among siblings. The rarity of the disease as well as the strong genetic etiology associated with it is an indication that it may have one or two variants that may confer the disease susceptibility in human beings. Common signs and symptoms of AAD may start at any point of the disease but are most likely to occur between the ages of 30 and 50. Common associated with the autoimmune disease includes nausea, fatigue, low blood pressure, weight loss, dizziness especially when one stands up too quickly, the skin may become abnormally dark in some areas a condition referred to as hyperpigmentation, lips as well as lining inside of the mouth tend to be dark. The disease also results in an imbalance of hormones associated with development of sexual characteristics and thus you may find a woman losing their underarm hairs or pubic hair.

90% of the damage caused to the endocrine organ renders the organ ineffective meaning it will not have the capability to produce sufficient steroids hormones, cortisol and aldosterone and once the levels of the three core hormones reduce, the symptoms of Addison’s manifest. Due to the underproduction of the cortisol hormone and aldosterone, Addison’s disease is otherwise known as chronic adrenal insufficiency or hypocortisolism. Some of the main functions of the cortical hormone include maintaining of blood pressure and the important cardiovascular functions, it also plays a critical role in aiding and balancing the work of insulin in ensuring the sugars are broken down to energy as well as ensuring the immune system inflammatory response is regulate. The hormone is also associated with the regulation of carbohydrates, proteins, and fat metabolism. Addison disease is also termed as autoimmune disease because it results from a malfunctioning immune system that produce cells to destroy other glands. The results are the destruction and disruption of other several hormones and hence affecting several other body systems.

Tuberculosis has also been termed as one of the main causes of the Addison’s disease, this is because Tb is a bacterial infection affecting the lungs and may at times affect other organs including the kidneys and in instances where the kidneys are affected then the adrenal glands responsible for important endocrine functions is damaged (Dabrowska, 2012). In many instances the Addison’s disease is also known as Autoimmune Addison’s Disease, it a rare condition and also has high chance of it being hereditary in comparison to other autoimmune conditions. Research demonstrates that the condition has a vivid and strong genetic connection and the characteristic make it possible for the disease to be hereditary. ADD may lead to an adrenal crisis that is often characterized by back pain, leg cramps, vomiting, severe low blood pressure that may lead to shock and abdominal pain. Often the adrenal crisis begins as a result of a stressor such as an infection, a surgery or even any kind of trauma. When the body experience stress, normally the adrenal gland will produce two to three times the amount of cortisol. However, for a person suffering from Addison disease, they have the inability to increase the amount of cortisol produced and thus the body cause to a crisis a condition referred to as addisonian crisis a life-threatening-situation.

Addison disease result when adrenal glands hence the hormone cortisol is not produced in the body as well as aldosterone. Adrenal glands are part of the endocrine system and have a part in production of hormones. Adrenal glands have the outer layer which is the cortex and the inner part which is the medulla. Cortex produce a group of hormones referred to as corticosteroids which include glucocorticoids, androgens and mineralocorticoids (Dalin, 2016). When the cortex becomes damaged it often does not produce adrenocortical hormones and the condition is known as primary adrenal insufficiency. This often leads to the body attacking itself and that is why the Addison disease is referred to as an autoimmune disease. The body begins viewing the adrenal cortex as a foreign object sand starts attacking and destroying it. There is

Adrenal dysgenesis is the development of congenital defects in the adrenal glands. In the normal development of the adrenal cortex, there are multiple genes that are required and if mutation occurs on any of these genes then an adrenal dysgenesis is likely to occur. There are various genes that have been identified to be important in the development of the adrenal cortex and they include nuclear hormone receptor superfamily a good example SF-1, DAX-1 which is the dosage-sensitive sex-reversal hypoplasia gene and ACTH receptor which is the melanocortin-2 receptor gene. When mutations occur in DAX-1, it may result in X-Linked congenital adrenal hypoplasia and hypogonadism (Suntharalingham, 2015). Adrenal hypoplasia is often present in males that have a life threatening adrenal crisis among newborns and hypogonadrophic hypogonadism in adolescent years.

The genetic variants known to lead to Addison’s disease, include those present at particular loci of the chromosomes such as MHC, MICA, CIITA, CTLA4, PTPN22, CYP27B1, NLRP-1 STAT4, GATA3 and CD274. Autoantibodies 21-hydroxylase (21OH-AA) has been identified as a factor that leads to progression of ADD. However, the highest genetic risk has been identified to be on the MHC, Major Histocompatibility region. The formation of 21OH-AA comes the development of Addison’s disease even with the absence of the symptoms and is a marker for the progression of the disease. 210H-AAA has been identified in progression of other autoimmune diseases such as thyroiditis and type 1 diabetes leading to the conclusion that these diseases may have a common pathophysiology.

SF-1 gene is necessary for the development of adrenal cortex the ventro-medial nucleus as well as the gonads and the gene is as a result of fushi turazu factor-1. SF-1 mutation is likely to result in adrenal insufficiency which eventually lead to Addison’s disease. In trying to establish how SF-1 resulted in adrenal agenesis, a mouse in vivo experiment was conducted and the Nr5al deleted. POR deficiency is a disorder of gonad and adrenal steroidogenesis which tends to affect microsomal cytochrome P450 enzymes (Suntharalingham, 2015). When partial mutations occur on POR t causes partial deficiencies to 21-hydroxylase, steroid 17a-hydroxylase, 17, and 20. Evidence has been presented of both cell-mediated and humoral mechanism which are often directed to adrenal cortex that destroys it. Antibodies get to react with the steroidogenic enzymes often 21-hydroxylse.

ACTH deficiency has been linked to be another cause of the Addison’s disease. ACTH deficiency arises from a decrease in the hormone adrenocorticotropic hormone produced by the pituitary gland. ACTH has been classified as a secondary adrenal insufficiency. Symptoms associated with ACTH include lack of appetite thus the patient is likely to be anorexic, weakness of muscles, nausea, low blood pressure and vomiting. Often concentration of 17-ketosteroids and 17-hydroxycorticosteroids that are produced by the adrenal cortex is often low. The congenital defect at birth characterized by the mutation of T-box 19 (TBX19) gene located on chromosome one and mutation also of corticotrophin releasing hormone (CRH) gene that is located on chromosome eight (Skinningsrud, 2008). When someone has ACTH, later in life they are likely to develop the Addison’s disease. This due to the chronic depletion of the adrenocortical function that results in deficiencies of mineralocorticoids and glucocorticoids. There are other factors that may result in secondary adrenal insufficiency including tumors in the central nervous system affecting release of hormones and necrosis of the pituitary gland after giving birth a condition referred to as Sheehan syndrome.

Addison disease has been found to have quite a strong genetic component but due to the fact that it is rare the recurrence rate in the family has been said to be at 2%. There are quite a number of disease-susceptibility alleles that have been pointed out that includes three loci linked with organ-specific autoimmunity and they include PTPN22, CTLA4 and MHC. Genetic variation in AIRE locus has also been pin pointed as a predisposing factor to ADD even when protein alteration does not occur (Su, 2008). MHC region on the chromosome 6 has proved to be an important factor for Addison disease in determining the risk of polygenic autoimmune disease. Most researchers have often pinpointed how AAD risk loci tend to vary between different populations and thus more research on the various risk loci needs to be conducted among various populations.

The treatment of Addison disease includes use of medication where one is given hormone replacement therapy thus replacing the levels of the steroid hormones that the body is unable to produce. In treatment of the disease, it involves the replacement of the cortisol which is at times administered in terms of tablets referred to as hydrocortisone or the prednisone. The dosing regimen has to be administered in such a way that it gets to mimic the natural concentration of the hormone cortisol. The quarter amount of a prednisolone may be used for the equal effects of glucocorticoid hormone same as the hydrocortisone. The treatment of the disease is lifelong which means a person with the condition is likely to be on the medication for the rest of their lives. An additional medicine referred to as fludrocortisone may be prescribed as it may be a replacement for the aldosterone that is missing (Bjornsdottir, 2013). On the prognosis, if well managed and one gets to take their medication as prescribed most people with the disease get to live a relatively normal life.

Thanks to research, Addison disease is no longer life threatening as it used to be. There have been drugs and therapies that have been developed that can help a person leave just a normal life. Individuals with ADD do not have to get TB as it used to be. The study of the molecular basis the researchers are trying to look into ways on how genes that resulted in the disease can be suppressed or how they can deal with the mutation hat result in adrenal failure are being modulated for example manipulation of the endogenous adrenocortical stem cell thus enhancing steroidogenesis. These kind of research is what has led to the development of medicines that mimic the hormones produced by the adrenal gland. Although Addison disease is among the rarest form of autoimmune disorders, researchers are putting work into it to look for ways to counter it.

References

Björnsdottir, S., Sundström, A., Ludvigsson, J. F., Blomqvist, P., Kämpe, O., & Bensing, S. (2013). Drug prescription patterns in patients with Addison’s disease: a Swedish population-based cohort study. The Journal of Clinical Endocrinology & Metabolism, 98(5), 2009-2018.

Dalin, F., Nordling Eriksson, G., Dahlqvist, P., Hallgren, Å., Wahlberg, J., Ekwall, O., … & Catrina, S. B. (2016). Clinical and immunological characteristics of autoimmune addison disease: a nationwide swedish multicenter study. The Journal of Clinical Endocrinology & Metabolism, 102(2), 379-389.

Dąbrowska, Anna Maria, Jerzy S. Tarach, and Maria Kurowska. “Addison’s disease due to tuberculosis of the adrenal glands–case report and review of the literature.” Medical and Biological Sciences 26.4 (2012): 55-60.

Erichsen, M. M., Løvås, K., Skinningsrud, B., Wolff, A. B., Undlien, D. E., Svartberg, J., … & Carlson, J. A. (2009). Clinical, immunological, and genetic features of autoimmune primary adrenal insufficiency: observations from a Norwegian registry. The Journal of Clinical Endocrinology & Metabolism, 94(12), 4882-4890.

Skinningsrud, B., Husebye, E. S., Pearce, S. H., McDonald, D. O., Brandal, K., Wolff, A. B., … & Undlien, D. E. (2008). Polymorphisms in CLEC16A and CIITA at 16p13 are associated with primary adrenal insufficiency. The Journal of Clinical Endocrinology & Metabolism, 93(9), 3310-3317.

Su, M. A., Giang, K., Žumer, K., Jiang, H., Oven, I., Rinn, J. L., … & Chang, A. (2008). Mechanisms of an autoimmunity syndrome in mice caused by a dominant mutation in Aire. The Journal of clinical investigation, 118(5), 1712-1726.

Suntharalingham, J. P., Buonocore, F., Duncan, A. J., & Achermann, J. C. (2015). DAX-1 (NR0B1) and steroidogenic factor-1 (SF-1, NR5A1) in human disease. Best practice & research Clinical endocrinology & metabolism, 29(4), 607-619.