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CHAPTER IINTRODUCTION1.1. BackgroundAddisons disease is a rare autoimmune dissease,1,2,3 that occurs when the adrenal glands do not produce enough of their hormones.1 Most of the cases in Addisons disease is caused by autoimmune disease (about 80% of total cases), 1,3,4,5 less common causes include granulomatous disease (eg sarcoidosis, tuberculosis), haematological malignancies, metastatic malignant disease, infiltrative metabolic disease (eg amyloidosis), congenital adrenal hyperplasia, abdominal radiation and the abrupt cessation of long-term steroid therapy.4 Those cases lead to destruction or disfunction of entire adrenal cortex.1,3Addisons disease has insidious onset (e.g. malaise, anorexia, diarrhea, weight loss, joint, and back pain)2,6,4 as the chronic primary adrenal insuffiency and acute manifestations, in the form of Addisonian crisis (e.g. orthostatic hypotension, fever, and hypoglycemia)6,4, that can be fatal if not properly recognized and treated,1,2 however, incidence of such causes of deaths is not known.1Further investigations, including anti-adrenal antibodies and radiologicalimaging of the adrenal glands, are required to determine the underlying cause. Treatment involves the lifelong replacement of glucocorticoid and mineralocorticoid.6,4,7Thomas Addison is the first person that describe this disease at 1855,3,8,5 in his classic paper, On the Constitutional and Local Effects of Disease of the Supra-Renal Capsules.8

CHAPTER IICONTENT2.1. Etiology and Pathogenesis of Addison DiseaseThe etiopathogenesis of primary adrenocortical insufficiency has changed over time. Prior to 1920, tuberculosis was the major cause of adrenocortical insufficiency. Since 1950, autoimmune adrenalitis with adrenal atrophy has accounted for about 80% of cases. It is associated with a high incidence of other immunologic and autoimmune endocrine disorders. Primary adrenocortical insufficiency, or Addison disease, is rare, with a reported prevalence of 35 to 140 per million population.92.1.1. Autoimmune Adrenocortical InsufficiencyAutoimmune Addison disease is frequently accompanied by other immune disorders. There are two different syndromes in which autoimmune adrenal insufficiency may occur. The best characterized one is known as autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome (APCED), or autoimmune polyglandular syndrome type 1 (APS-1). This is an autosomal recessive disorder that usually presents in childhood and is accompanied by hypoparathyroidism, adrenal failure, and mucocutaneous candidiasis. APS-1 results in most cases from a mutation of the autoimmune regulator gene (AIRE), which is located on chromosome 21q22.3. Autoantibodies against the cholesterol side chain cleavage enzyme (P450scc, CYP11A1) and others have been described in patients with this disorder.9 The more common presentation of autoimmune adrenocortical insufficiency is associated with HLA-related disorders including type 1 diabetes mellitus and autoimmune thyroid disease. Other less common related disorders include alopecia areata, vitiligo, primary hypogonadism, pernicious anemia, and celiac disease. This disorder is often referred to as APS type 2. The genetic susceptibility to this disorder is linked to HLA-DR3 or DR4 (or both). These patients have antiadrenal cytoplasmic antibodies that may be important in the pathogenesis of this disorder and autoantibodies against 21-hydroxylase (p450C21, CYP21A2)9,10,2.1.2. InfectionTuberculosis and fungal infections are associated with enlarged adrenals that may show calcifications. Of note, the azole antifungal agents, such as ketoconazole, inhibit adrenal cytochrome P450 steroidogenic enzymes that are essential for cortisol biosynthesis. Thus, azole antifungal treatment, especially with ketoconazole, in patients with marginal adrenocortical reserve due to fungal disease may precipitate adrenal crisis.10HIV/AIDS has been associated with pathologic involvement of the adrenal gland. Primary adrenal insufficiency in AIDS is usually caused by opportunistic infections such as fungal infection, cytomegalovirus, and mycobacterium avium complex. Adrenocortical insufficiency usually occurs as a late manifestation in AIDS patients with very low CD4 counts.10,112.2. Pathophysiology of Addison DiseaseAddisons disease only affects the cortex portion of the adrenal glands; it causes deficiency of hormone that is produced there, including mineralocorticoid (aldosterone), glucocorticoid (cortisol), and adrenal androgen. 2.2.1. Mineralocorticoid (Aldosterone)Aldosterone has function mainly to maintain electrolyte balance by increasing natrium and chloride reabsorption and also increasing kalium secretion in renal tubules epithelium. Deficiency of aldosterone causes hyponatremia that followed by hyperkalemia in extracellular fluid significantly. Decreasing extracellular fluid total volume leads to low plasma volume and hypotension. Shock will present when cardiac output decreases. In severe hyperkalemic condition (60-100% above normal), cardiac contraction weakness and arrhythmia can be clearly seen.12Aldosterone also stimulates hydrogen secretion that will be changed with natrium in renal. Increasing hydrogen concentration in extracellular fluid can cause mild acidosis. Another function of aldosterone is increasing natrium absorption in intestine, mainly in colon. Failure of this function will be followed by failure of kalium, another anion, and water absorption; the patient will suffers from diarrhea and so will presents sign of dehydration.122.2.2. Glucocorticoid (Cortisol)Cortisol plays a role in carbohydrate, protein, and lipid metabolism. In carbohydrate metabolism, cortisol stimulates gluconeogenesis in the liver by increasing enzymes that is needed to this process and transporting amino acid from extrahepatic tissue. It also reduces cellular glucose usage by unknown mechanism. In protein metabolism, cortisol increases level of liver protein and plasma protein by suppressing amino acid mobilization into extrahepatic tissue. It reduces protein synthesize, but protein catabolism continues inside the cell, so tissue protein deposit will decrease. In lipid metabolism, cortisol helps in increasing fatty acid mobilization from adipose tissue. So, suppression of many metabolism functions will be happened in Addisons disease, results in fatigue and weakness.12 In the correlation of metabolism, patient with Addisons disease may presents with hypoglycemic, weight loss, and muscle weakness. Decreasing cortisol secretion reduces blood glucose, thus will cause hypoglycemic. Low blood glucose triggers insulin secretion to drop. Beside its function in glucose uptake, insulin can also stimulates triglyceride storage, so the patient will experienced weight loss. Muscle weakness is resulted from lack of ATP because of low glucose. Cortisol is one of orexigenic substance or appetite stimulant; it correlates with complain of loss of appetite from patient with Addisons disease.12,13Cortisol is important in managing the body to react with stress, including trauma, inflammation, infection, surgery, emotional, etc. In cortisol deficiency, the patient with extreme stressful events may present with severe illnesses. Cortisol is also found to stimulates erythrocyte production by unknown mechanism; the patient will show anemia signs in Addisons disease.13When Adrenocorticotropin Hormone (ACTH) was secreted from anterior hypophysis gland, another hormone that has same chemical characteristics, such as Melanocyte Stimulating Hormone (MSH), will also be secreted too because those hormones have same precursor. In normal condition, MSH did not give significant effect on human body because it was secreted only in small amount. If ACTH is rapidly secreted because of low level plasma cortisol, secretion of MSH will be increased too. This condition leads to overstimulation of melanin formation or hyperpigmentation in skin and mucous membrane.12,14,15 2.2.3. Adrenal AndrogenBesides mineralocorticoid and glucocorticoid, adrenal cortex also secretes sex hormone--adrenal androgen, which has same effects with testosterone. Because it secreted in small amount, deficiency in this hormone did not produce significant features. Women may have loss of androgen-stimulated hair, such as pubic and axillary hair, and irregular or absent menstrual periods. Men do not have hair loss because male androgen is produced primarily in testes.12,13,162.3. Clinical Presentation of Addison DiseaseAddison disease presents insidiously with nonspecic symptoms that easily can be mistaken for other more prevalent conditions. For example, its common symptoms, chronic fatigue, malaise, and anorexia may mimic a depressive illness. Likewise, unintentional weight loss, nausea, vomiting, and vague abdominal pain may be confused with symptoms of a gastrointestinal or eating disorder. Symptoms of postural hypotension (syncope, postural dizziness) and hypoglycemia are late manifestations of the disease. Pigmentation of skin and mucous membranes, when present, is a cardinal sign of Addison disease.17 Several biochemical abnormalities may provide a clue to the diagnosis of Addison disease. In a patient with unexplained hyponatremia, adrenal insufciency must be excluded before making the diagnosis of syndrome of inappropriate antidiuretic hormone secretion. Likewise, in a patient with unexplained hyperkalemia, Addison disease must be considered as a possibility before treating the patient with insulin and dextrose infusion. Some patients with Addison disease show a raised serum thyrotropin level at presentation. The diagnosis of Addison disease must be considered in a hypothyroid patient whose symptoms worsen after starting thyroxine.18 Furthermore, unexplained recurrent hypoglycemic episodes in a patient with type 1 diabetes should also raise a suspicion of Addison disease. About half of patients with Addison disease present acutely with adrenal crises. This is a life-threatening emergency characterized by severe dehydration and circulatory shock. Many patients also have nausea, vomiting, and abdominal pain, which may lead to a misdiagnosis of an acute abdomen. Acute adrenal crisis is usually precipitated by infection or other forms of severe physiological stress.192.4. Diagnosis of Addison Disease2.4.1. Anamnesis and Physical ExaminationPatient with Addisons disease usually comes with non-specific complains, such as Loss of appetite and weight, nausea, vomiting or diarrhea, muscle weakness, fatigue, lightheadedness, chronic-worsening fatigue, salt cravings, dehydration, abdominal pain, irregular or no menstrual periods in women, mood swings, mental confusion or loss of consciousness. Low blood pressure (hypotension), Increased pigmentation of the skin, particularly around scars and bony areas, loss of pubic and axillary hair in women.2.4.2. Laboratory ResultIn the early phase of gradual adrenal destruction, there may be no demonstrable abnormalities in the routine laboratory parameters. In more advanced stage of adrenal destruction, serum sodium, chloride, and bicarbonate levels are reduced, and the serum potassium level is elevated. The hyponatremia is due both to loss sodium into the urine. This extravascular sodium loss depletes extracellular fluid volume and accentuates hypotension. Elevated plasma vasopressin and angiotensin II levels may contribute to the hyponatremia. Hyperkalemia is due to a combination of aldosterone deficiency, impaired glomerular filtration, and acidosis. Basal level of cortisol and aldosterone are subnormal and fail to increase following ACTH administration. There may be a normocytic anemia, a relative lymphocytosis, and a moderate eosinophilia.The diagnosis of adrenal insufficiency should be made only with ACTH stimulation testing to assess adrenal reserve capacity for steroid production. In brief, the best screening test is the cortisol response 60 min after 250 g of cosyntropin given intramuscularly or intravenously. Cortisol level should exceed 495 nmol/L (18 g/dL). If the response is abnormal, then primary and secondary adrenal insufficiency can be distinguish by measuring aldosterone levels from the same blood sample. Furthermore, in primary adrenal insufficiency, plasma ACTH and associated peptides (-LPT) are elevated because of loss the usual cortisol-hypothalamic-pituitary feedback relationship.20Antiadrenal antibodies are found in most cases of idiopathic Addisons disease but in minority of those due to adrenal tuberculosis. Said to have very high sensitivity, specificity, and predictive value for development of adrenocortical failure in women with normal adrenal adrenocortical function.21 In patients suspected of having an Addisonian crisis, health professionals must begin treatment with injections of salt, glucose-containing fluids, and glucocorticoid hormones immediately. Although a reliable diagnosis is not possible during crisis treatment, measurement of blood ACTH and cortisol during the crisis-before glucocorticoids are given-is enough to make a preliminary diagnosis. Low blood sodium, low blood glucose, and high blood potassium are also usually present at the time of an adrenal crisis. Once the crisis is controlled, an ACTH stimulation test can be performed to obtain the specific diagnosis.222.4.3. Imaging In Addison disease from an autoimmune abnormality, the adrenal gland is small at CT. A second cause of Addison disease is replacement of the adrenal gland by either neoplasm, hemorrhage, or infection, the adrenal gland is often enlarged. The adrenal masses caused by granulomatous disease or hemorrhage may involute and subsequently calcify.23

2.5. Differential Diagnosis 2.5.1. Adrenal CrisisAdrenal crisis is an acute adrenal insufficiency, which occurs if the level of cortisol hormone is decreasing suddenly, and can lead to death if it doesnt treat immediately. The difference of Addisons disease and adrenal crisis is the symptoms. Symptoms in Addisons disease develop slowly, over months to years, with weakness, fatigue, anorexia, weight loss, and hyperpigmentation as the primary symptoms. In contrast, symptoms of adrenal crisis occur acutely, can manifest with vomiting, abdominal pain, and hypovolemic shock.24,252.5.2. Adrenal HemorrhageAdrenal hemorrhage is a relatively uncommon condition with a variable and nonspecific presentation that may lead to acute adrenal crisis, shock, and death unless it is recognized promptly and treated appropriately. It can result from a variety of causes (traumatic as well as non traumatic), When unilateral,itis often clinically silent. In contrast, bilateral adrenal hemorrhage can lead to catastrophic adrenal insufficiency.26,272.5.3. C-17 Hydroxylase DeficiencyIt is the rare variant of congenital adrenal hyperplasia. Patients with 17-hydroxylase deficiency have alterations in their CYP17 gene, which encodes the P450C17 enzyme, enzyme that found in the zona reticularis of the adrenal cortex and plays a central role in steroidogenesis. Steroidogenesis is essential for the production of cortisol and sex steroids. Thus, patient with 17-hydroxylase deficiency have reduced secretion of cortisol, androgen, and estrogen, with adrenal and gonadal steroidogenesis impairment.28,292.6. Treatment of Addison DiseaseThe primary goal of treatment is to overcome glucocorticoid and mineralocorticoid deficiencies.302.6.1. Glucocorticoid ReplacementHydrocortisone is most commonly used for glucocorticoid replacement. Long-acting glucocorticoids, dexamethasone, and prednisolone have the advantage of a once-daily dosing schedule but have the drawback of losing the diurnal pattern, resulting in excess glucocorticoid levels overnight.30 In the chronic cases, prednisone or prednisolone are preferably performed, glucocorticoids with reduced mineralocorticoid effect and lower incidence of myopathy than fluorinated glucocorticoids (e.g. dexamethasone).31In Addison disease, standard replacement dose of hydrocortisone is 15-25 mg a day, given in 2 or 3 divided doses (10 mg on waking, 5 mg at noon, 5 mg early evening). In practice, the dose of hydrocortisone is maintained on the basis of clinical assessment, taking an account of patients wellbeing, and presence of any signs of over-replacement (eg, hypertension, weight gain, thin skin, easy bruising, and glucose intolerance) or under-replacement (eg, weight loss and pigmentation).302.6.2. Mineralocorticoid Replacement Fludrocortisone is the only available agent for mineralocorticoid replacement. The usual starting dose is 100 gram a day. The dose is adjusted (usually 50-200 gram a day) according to clinical response. Hypertension and presence of ankle edema suggest over-replacement, while salt craving, postural hypotension, and hyperkalemia are signs of under-replacement..302.6.3. Management of an Adrenal CrisisAn adrenal crisis is a life-threatening medical emergency that requires urgent hospital admission for treatment with intravenous hydrocortisone and crystalloid. Patients may need several liters of normal saline to maintain their blood pressure. The recommended initial dose of hydrocortisone is 100 mg, with subsequent doses of 100-200 mg over 24 hours divided into 3 or 4 doses.302.7. Complication of Addison DiseaseAdrenal crisis is a medical emergency and must be treated immediately.32 If it is left untreated, it can lead to coma and death. Adrenal crisis can cause: cardiac arrest: when the heart stops completely stroke: when the blood supply to the brain is interrupted hypovolemic shock: when severe blood and fluid loss means that your heart cannot pump enough blood around your body hypoxia: when the bodys tissues do not get enough oxygenIf any of organs or tissues, including brain, do not get enough oxygen, it can cause permanent disability(an injury which impairs the physical and mental ability of a person to perform normal work for the remainder of their life).33

CHAPTER IIICONCLUSIONAddisons disease is a rare autoimmune dissease, that occurs when the adrenal glands do not produce enough of their hormones.1 Most of the cases in Addisons disease is caused by autoimmune disease (about 80% of total cases), less common causes include granulomatous disease (eg sarcoidosis, tuberculosis), haematological malignancies, metastatic malignant disease, infiltrative metabolic disease (eg amyloidosis), congenital adrenal hyperplasia, abdominal radiation and the abrupt cessation of long-term steroid therapy. Those cases lead to destruction or disfunction of entire adrenal cortex.Deficiency of aldosterone causes hyponatremia, hyperkalemia, low plasma volume, mild acidosis, and diarrhea. Deficiency of cortisol causes hypoglycemic, weight loss, muscle weakness, loss of appetite, failure to react with stress, anemia, and hyperpigmentation. Deficiency of adrenal androgen causes less significant effects.Treatment to decrease severity to the patient who are suffering from addison disease including glucocorticoid replacement, mineralocorticoid replacement, management of an adrenal crisis. Adrenal crisis is a medical emergency and must be treated immediately. If it is left untreated, it can lead to coma and death. Adrenal crisis can cause.