Thomas Addison이 Addison’s disease를 기술했을 때 (1855년)에는 결핵에 의한 bilateral adrenal destruction이 가장 흔한 원인이었습니다. 이제 결핵은 모든 케이스의 7-20 %에 지나지 않고 70-90%는 자가면역이며 나머지가 다른 감염 원인, 암, 림프종, 부신 출혈 또는 경색, 약물들입니다.
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The story of ‘Addison’s disease’ begins with the adrenal glands, first described by Eustachius in 1714. Addison first wrote a short article in the London Medical Gazette (1849): ‘Anaemia—disease of the suprarenal capsules in which the disease is not distinctly separated from a new form of anaemia’. Then, in 1855, came his monograph, one of the unsurpassed medical works of the nineteenth century. Addison describes here for the first time two chronic diseases which he could not clearly separate—‘On the Constitutional and Local Effects of Disease of the Suprarenal Capsule’ The entity he related was doubted by Hughes Bennett (1812-1875) in Edinburgh but confirmed by Trousseau (1801-1867) in Paris, who recognized suprarenal failure and named it Addison's disease. The monograph describes how, when investigating a peculiar form of anaemia, he found pathological changes in both suprarenal glands that appeared to be independent of the anaemia. He had with Samuel Wilks collected 11 patients. J R Soc Med. 2004 Jun; 97(6): 297–300 |
Congenital adrenal hyperplasia (CAH) (선천성 부신증식증 [부신과형성])는 다음과 같은 여러 부신 부전 원인들 중의 하나입니다.
(Mixed Mineralocorticoid and Glucocorticoid Deficiency: Adrenal Insufficiency)
Causes of adrenal insufficiency (Addison's disease)
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Autoimmune adrenalitis |
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Isolated adrenal insufficiency |
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Polyglandular autoimmune syndrome type I |
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Polyglandular autoimmune syndrome type II |
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Infectious adrenalitis |
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Tuberculosis |
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Disseminated fungal infection |
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Histoplasmosis |
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Paracoccidioidomycosis |
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HIV infection and AIDS |
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Syphilis |
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African trypanosomiasis |
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Metastatic cancer |
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Primarily lung, breast, stomach and colon cancer or lymphoma |
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Adrenal hemorrhage or infarction |
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Drugs |
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Ketoconazole |
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Fluconazole |
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Rifampin |
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Phenytoin |
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Barbiturates |
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Megestrol acetate |
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Other: aminoglutethimide, etomidate, metyrapone, suramin, mitotane |
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Other |
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Adrenoleukodystrophy and adrenomyeloneuropathy |
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Congenital adrenal hypoplasia |
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Familial glucocorticoid deficiency |
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Familial glucocorticoid resistance |
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Defective cholesterol metabolism |
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Congenital Adrenal Hyperplasias (선천성 부신증식증 [부신과형성]) The congenital adrenal hyperplasias are a disparate group of diseases caused by a genetic deficiency of one of the enzymes needed for adrenal steroidogenesis. Patients with nearly complete deficiency of an enzyme required for cortisol synthesis present in infancy with adrenal insufficiency and salt-wasting crisis. This is most problematic in patients with mutation of the 21-hydroxylase ( CYP21A2 ) or 11β-hydroxylase ( CYP11B1 ) gene. The increase in ACTH levels caused by cortisol deficiency drives the intact steroidogenic pathways so that there is excessive production of the steroids just proximal to the enzymatic block—17-hydroxyprogesterone and 11-deoxycortisol, respectively, in 21-hydroxylase and 11β-hydroxylase deficiency. The increased levels of precursor steroids enable increased adrenal androgen synthesis, so that severely affected girls may be virilized in utero. Girls and women with nonclassic congenital adrenal hyperplasia present later. They have greater enzyme activity, so that cortisol production is adequate, but increased ACTH levels cause hyperandrogenism. 1. Adrenal steroidogenesis에 필요한 효소들 중의 하나가 유전적으로 결핍되어 생기는 이질적인 그룹의 질환입니다. 2. 가장 흔한 형태의 효소 결핍은 21-hydroxylase ( CYP21A2 ) 또는 11β-hydroxylase ( CYP11B1 )입니다. 3. 코티솔 결핍되어 상승된 ACTH는 intact steroidogenic pathways를 촉진시켜 차단된 경로 바로 직전의 steroids를 과도하게 생성합니다. 21-hydroxylase가 결핍된 경우는 17-hydroxyprogesterone이 과도하게 생성되고, 11β-hydroxylase가 결핍된 경우에는 11-deoxycortisol이 과도하게 생성됩니다. 이로 인해 precursor steroids가 증가하면 adrenal androgen synthesis가 증가됩니다. Goldman-Cecil Medicine 26th edition |
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개념 이해에 대한 문단입니다. 코티솔 합성이 부적절해지면 시상하부와 뇌하수체에 신호를 주어 CRH, ACTH 분비를 증가시키고 결과적으로 부신이 비대해지며 차단된 경로의 직전에 있는 스테로이드 전구체가 축적됩니다. 이 전구체가 안드로젠으로 바뀌어 성과 관련된 증상을 나타냅니다. The fundamental defect among patients with any form of congenital adrenal hyperplasia is inadequate synthesis of cortisol. Inefficient cortisol synthesis signals the hypothalamus and pituitary to increase corticotropin-releasing hormone and ACTH, respectively. Consequently, the adrenal glands become hyperplastic, and steroid precursors accumulate proximal to the block in biosynthesis. In some conditions, these precursors can be converted to androgens. |
결핍된 효소에 따라 여러 가지 이질적인 형태를 나타냅니다 (Variants of Congenital Adrenal Hyperplasia (선천성 부신증식증 [부신과형성])).
CYP21A2 (21-hydroxylase)가 결핍되면 17-hydroxyprogesterone이 과도하게 형성됩니다.
Synthetic defect in CYP21A2 (21-hydroxylase) deficiency
Pathways of adrenal steroid synthesis. A synthetic defect in 21-hydroxylase leads to diminished cortisol synthesis, increased release of corticotropin (ACTH), accumulation of 17-hydroxyprogesterone (particularly after the administration of ACTH), possible virilization due to increased androgen production, and possible salt-wasting due to diminished production of aldosterone and deoxycorticosterone.
Congenital adrenal hyperplasia related to 21-hydroxylase deficiency. The normal synthesis of cortisol is impaired, and adrenocorticotropic hormone (ACTH) levels increase because of loss of normal negative feedback inhibition, resulting in an increase in adrenal steroid precursors proximal to the block. The results are cortisol deficiency, variable mineralocorticoid deficiency, and excessive secretion of adrenal androgens. CYP, cytochrome P450; DHEA, dehydroepiandrosterone; DOC, deoxycorticosterone; HSD, hydroxysteroid dehydrogenase; StAR, steroidogenic acute regulatory protein.
다음 그림은 학생 때부터 보아 온 부신 스테로이드 합성에 대한 표입니다. 앞의 2가지 표와 비슷합니다.
21-Hydroxylase Deficiency는 21-Hydroxylase activity 정도에 따라 유형을 구분할 수 있습니다.
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21-HYDROXYLASE DEFICIENCY (CONGENITAL ADRENAL HYPERPLASIA) The classic form of 21-hydroxylase deficiency (21-OHD) is the most common cause of CAH. It has an incidence between 1 in 10,000 and 1 in 15,000 and is the most common cause of androgenization in chromosomal 46,XX females. Affected individuals are homozygous or compound heterozygous for severe mutations in the enzyme 21-hydroxylase (CYP21A2). This mutation causes a block in adrenal glucocorticoid and mineralocorticoid synthesis, increasing 17-hydroxyprogesterone and shunting steroid precursors into the androgen synthesis pathway. Glucocorticoid insufficiency causes a compensatory elevation of adrenocorticotropin (ACTH), resulting in adrenal hyperplasia and additional synthesis of steroid precursors proximal to the enzymatic block. Increased androgen synthesis in utero causes androgenization of the 46,XX fetus in the first trimester. Ambiguous genitalia are seen at birth, with varying degrees of clitoral enlargement and labial fusion. Excess androgen production causes gonadotropin-independent precocious puberty in males with 21-OHD. The salt-wasting form of 21-OHD results from severe combined glucocorticoid and mineralocorticoid deficiency. A salt-wasting crisis usually manifests between 5 and 21 days of life and is a potentially life-threatening event that requires urgent fluid resuscitation and steroid treatment. Thus, a diagnosis of 21-OHD should be considered in any baby with atypical genitalia with bilateral nonpalpable gonads. Males (46,XY) with 21-OHD have no genital abnormalities at birth but are equally susceptible to adrenal insufficiency and salt-losing crises. Females with the classic simple virilizing form of 21-OHD also present with genital ambiguity. They have impaired cortisol biosynthesis but do not develop salt loss. Patients with nonclassic 21-OHD produce normal amounts of cortisol and aldosterone but at the expense of producing excess androgens. Hirsutism (60%), oligomenorrhea (50%), and acne (30%) are the most common presenting features. This is one of the most common recessive disorders in humans, with an incidence as high as 1 in 100 to 500 in many populations and 1 in 27 in Ashkenazi Jews of Eastern European origin. Biochemical features of acute salt-wasting 21-OHD are hyponatremia, hyperkalemia, hypoglycemia, inappropriately low cortisol and aldosterone, and elevated 17-hydroxyprogesterone, ACTH, and plasma renin activity. Presymptomatic diagnosis of classic 21-OHD is now made by neonatal screening tests for increased 17-hydroxyprogesterone in many centers. In most cases, 17-hydroxyprogesterone is markedly increased. In adults, ACTH stimulation (0.25 mg of cosyntropin IV) with assays for 17-hydroxyprogesterone at 0 and 30 min can be useful for detecting nonclassic 21-OHD and heterozygotes. Harrrison's Internal Medicine 20th edition |
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파란색 글씨는 해리슨 20판에서 nonclassic 21-OHD에 대한 내용입니다. 이 유형에서는 코티솔과 알도스테론이 정상이고 안드로젠이 과생성되어 있으며 hirsutism (60%), oligomenorrhea (50%), acne (30%)가 특징입니다. ACTH stimulation (0.25 mg of cosyntropin IV) with assays for 17-hydroxyprogesterone at 0 and 30 min 검사를 통해 진단합니다.
이 유형은 childhood 또는 early adulthood 때 premature pubarche로 내원하거나 polycystic ovary syndrome (PCOS)과 닮은 임상증상을 나타내기도 합니다. 실제로 nonclassic 21-hydroxylase deficiency는 PCOS 2차 원인들 중의 하나이고 classic variant보다 훨씬 흔합니다.
Williams Textbook of Endocrinology, 14th edition
Nonclassic or Late-Onset 21-Hydroxylase Deficiency
Patients with nonclassic 21-hydroxylase (NCAH) deficiency present in childhood or early adulthood with premature pubarche or with a phenotype that may masquerade as polycystic ovary syndrome (PCOS). Indeed, nonclassic 21-hydroxylase deficiency is a recognized secondary cause of PCOS and is far more common than the classic variant. Some evidence suggests that at least 30% of adult patients have an impaired cortisol response to ACTH(1-24) and may be prone to stress-induced adrenal insufficiency, but the rates of adrenal crises in untreated patients appear to be very low. There is overlap in the effects of mutations that cause NCAH and classic 21-hydroxylase deficiency, and if patients fail an SST they are better characterised as occult classic 21-hydroxylase deficiency. In some series from tertiary referral centers, nonclassic 21-hydroxylase deficiency accounts for up to 12% of all PCOS patients, but more realistic prevalence rates are probably 1% to 3%. Females present with hirsutism, primary or secondary amenorrhea, or anovulatory infertility. Androgenic alopecia and acne may be other presenting features.
진단을 위해 17OHP을 측정합니다.
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A very high serum concentration of 17OHP in a randomly timed blood sample is diagnostic of classic 21-hydroxylase deficiency. Most affected neonates have random concentrations greater than 3500 ng/dL (105 nmol/L). All have concentrations greater than 1200 ng/dL (36 nmol/L). 17OHP may be elevated in 11-beta-hydroxylase deficiency, but levels are <1200 ng/dL (36 nmol/L). |
Nonclassic or Late-Onset 21-Hydroxylase Deficiency 진단을 위해서도 early morning baseline 17-hydroxyprogesterone이 좋은 스크리닝 검사이고 ACTH test 검사 필요성을 없앨 수도 있습니다.
In children, a 17-hydroxyprogesterone level of >200 ng/dL (6 nmol/L) taken at 8:00 AM has 92 to 98 percent sensitivity and specificity for the diagnosis of nonclassic 21-hydroxylase deficiency. The early morning timing is critical because the 17-hydroxyprogesterone level falls rapidly during the course of the day.
In adult women, the diagnosis of NCCAH is strongly suggested by a basal 17-hydroxyprogesterone value greater than 200 ng/dL (6 nmol/L) and confirmed with an ACTH stimulation test.
Nonclassic or Late-Onset 21-Hydroxylase Deficiency과 관련하여 누구에게 이런 검사를 해야 하는가?
높은 농도의 17-hydroxyprogesterone을 확인하거나 ambiguous genitalia, salt wasting과 같은 임상 소견을 통해서 neonatal screening에서 진단되는 classic 21-hydroxylase deficiency와 달리 대부분의 nonclassic form은 neonatal screening에서 확인되지 않습니다. 따라서 nonclassic 21-hydroxylase deficiency에 대한 검사는 이 질환의 전형적인 소견을 나타내는 소아와 성인에서 고려되어야 합니다 .
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Children – Children with premature pubarche or accelerated growth velocity (crossing growth percentiles) with advanced bone age. |
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Men – A subset of males with NCCAH present in childhood with premature pubarche, accelerated growth velocity, and advanced bone age; however, many males with NCCAH remain asymptomatic and are never diagnosed. Some men are identified because they are tested following the diagnosis of a family member. Although most men with the nonclassic form have normal testicular function and normal fertility, testicular adrenal rests and infertility have been reported in rare isolated case reports. However, we do not suggest routine screening for NCCAH in men with infertility. |
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Women – Women with oligomenorrhea and hyperandrogenism (acne and/or hirsutism) because the clinical presentation of the nonclassic form of congenital adrenal hyperplasia (NCCAH) can be indistinguishable from that of polycystic ovary syndrome (PCOS). The prevalence of NCCAH in women who present with apparent PCOS is variable, depending upon the population studied. Testing for NCCAH is most important in higher-risk groups including Mediterranean, Hispanic, and Ashkenazi Jewish women. Some experts suggest testing for NCCAH only in high-risk populations, but we suggest measuring a basal 17-hydroxyprogesterone in all women who present with a PCOS-type picture. |
REF.
1. Williams Textbook of Endocrinology, 14th edition
2. Harrison's Internal Medicine, 20th edtion
3. Goldman-Cecil Medicine, 26th edition
4. UpToDate 2020.08.01
