疾患詳細

疾患詳細





%240200
Hypoadrenocorticism, familial
(Adrenal hypoplasia)
(Adrenal aplasia)
(Addison disease)

副腎皮質機能低下, 家族性
(副腎低形成)
(副腎無形成)
(アジソン病)
指定難病83 アジソン病

遺伝子座:不明
遺伝形式:常染色体劣性

(症状)
(GARD)
 <100%>
 Decreased circulating cortisol level (コルチゾール減少) [HP:0008163] [2147]
 
 <80%-99%>
 Abdominal pain (腹痛) [HP:0002027] [01420]
 Anorexia (食思不振) [HP:0002039] [01401]
 Constipation (便秘) [HP:0002019] [01803]
 Diarrhea (下痢) [HP:0002014] [01806]
 Failure to thrive (成長障害) [HP:0001508] [01411]
 Fatigue (疲労) [HP:0012378 ) [01410]
 Hyperpigmentation of the skin (皮膚高色素) [HP:0000953] [18017]
 Increased circulating ACTH level (ACTH 増加) [HP:0003154] [21141]
 Muscle weakness (筋力低下) [HP:0001324] [0270]
 Nausea and vomiting (悪心嘔吐) [HP:0002017] [01425]
 Weight loss (体重喪失) [HP:0001824] [01411]
 
 <30%-79%>
 Androgen insufficiency (アンドロゲン不全) [HP:0008226] [2153]
 Decreased circulating aldosterone level (アルドステロン減少) [HP:0004319] [2149]
 Decreased urinary potassium (尿中カリウム減少) [HP:0012364]
 Hyperkalemia (高カリウム血症) [HP:0002153] [2015]
 Hyperkalemic metabolic acidosis (高カリウム血症性代謝性アシドーシス) [HP:0002149] [2000]
 Hyponatremia (低ナトリウム血症) [HP:0002902] [2021]
 Increased circulating renin level (レニン増加) [HP:0000848] [2162]
 Normocytic anemia (正球性貧血) [HP:0001897] [2201]
 Renal salt wasting (腎性塩類喪失) [HP:0000127]
 
 <5%-29%>
 Adrenal calcification (副腎石灰化) [HP:0010512] [2141]
 Adrenal hypoplasia (副腎低形成) [HP:0000835] [2144]
 Arthralgia (関節痛) [HP:0002829] [15115]
 Celiac disease (セリアック病) [HP:0002608] [12318]
 Decreased female libido (女性リビド減少) [HP:0030018]
 Delayed puberty (思春期遅発) [HP:0000823] [2152]
 Dry skin (乾いた皮膚) [HP:0000958] [18039]
 Generalized bone demineralization (全身性骨ミネラル減少) [HP:0006462] [160015]
 Hashimoto thyroiditis (橋本甲状腺炎) [HP:0000872] [2124]
 Hypercalcemia (高カルシウム血症) [HP:0003072] [2007]
 Hypoglycemia (低血糖) [HP:0001943] [2014]
 Hypoparathyroidism (副甲状腺機能低下症) [HP:0000829] [2131]
 Orthostatic hypotension (起立性低血圧) [HP:0001278] [01416]
 Premature ovarian insufficiency (早期卵巣機能不全) [HP:0008209] [1406]
 Salt craving (食塩渇望) [HP:0030083]
 Seizures (けいれん) [HP:0001250] [01405]
 Sparse axillary hair (疎な腋毛) [HP:0002215] [1740]
 Type I diabetes mellitus (I 型糖尿病) [HP:0100651] [2013]
 Vertigo (眩暈] [HP:0002321] [01427]
 Vitiligo (白癜風 (白斑)) [HP:0001045] [18014]
 
 <1%-4%>
 Primary testicular failure (原発性精巣機能不全) [HP:0008720] [21500]
 Thiamine-responsive megaloblastic anemia (チアミン反応性巨赤芽球性貧血) [HP:0004860] [2201]
 Thymoma (胸腺腫) [HP:0100522] [2221]
 
 
 Abnormality of skin pigmentation (皮膚色素異常) [HP:0001000] [-]
 Abnormality of the cardiovascular system (心血管系異常) [HP:0001626] [1120]
 Adrenal insufficiency (副腎不全) [HP:0000846] [2145]
 Autosomal recessive inheritance (常染色体劣性遺伝) [HP:0000007]
 Cyanosis (チアノーゼ) [HP:0000961] [01406]
 Feeding difficulties in infancy (哺乳障害, 乳児期) [HP:0008872] [01411]
 Vomiting

(UR-DBMS)
【一般】成長障害
 *けいれん
 *チアノーゼ
 食餌摂取困難
 *新生児無呼吸発作
 *嘔吐
 血管破綻
 早期死亡
【性器】停留精巣
【毛髪】皮膚色素沈着
【検査】*低血糖
 *高カリウム血症
 *低ナトリウム血症
【内分泌】ゴナドトロピン欠損
 思春期遅発
 先天性副腎低形成
 副腎不全
 *コルチゾール/17-OHCS/17-KS 低値,アルドステロン低値
 ACTH への反応なし
<指定難病 アジソン病>
概要
 原発性の慢性副腎不全は 1855 年英国の内科医である Thomas Addison により初めて報告された疾患で あることから, Addison 病とも呼ばれている。その後, この原発性慢性副腎皮質機能低下症の病因として, 副腎皮質ステロイド合成酵素欠損症による先天性副腎皮質過形成症, 先天性副腎低形成(X 連鎖性, 常染色体性), ACTH不応症などが同定され責任遺伝子も明らかにされ先天性のものはアジソン病とは独立した 疾患単位として扱われるようになった。このため, アジソン病は後天性の成因による病態を総称する用語と して用いられている。

原因
 病因として原因不明の特発性と, 感染症あるいはその他原因によるものとがある。特発性アジソン病は自 己免疫性副腎皮質炎による副腎皮質低下症であり, しばしば他の自己免疫性内分泌異常を合併し多腺性自己免疫症候群と呼ばれている。これには特発性副甲状腺機能低下症, 皮膚カンジダ症を合併するⅠ型(HAM症候群)と, 橋本病などを合併するⅡ型(Schmidt 症候群)がある。特発性アジソン病では抗副腎抗体 陽性のことが多く(60~70%), ステロイド合成酵素の P450c21, P450c17 などが標的自己抗原とされている。 感染症に続発するものでは, 結核性が代表的であるが, 真菌性や後天性免疫不全症候群(AIDS)に合併 するものが増えている。しかし, 感染の後に全員に発生するわけでは無く, 発症の機序も不明である。

症状
 副腎皮質ホルモンの欠落により, 易疲労感, 全身倦怠感, 脱力感, 筋力低下, 体重減少, 低血圧などが みられる。食欲不振, 悪心・嘔吐, 下痢などの消化器症状, 精神症状(無気力, 不安, うつ)など様々な症状 を訴える。いずれも非特異的な症状である。色素沈着は皮膚, 肘や膝などの関節部, 爪床, 口腔内にみら れる。

治療法
 急性副腎不全の発症時には, グルココルチコイドとミネラルコルチコイドの速やかな補充と, 水分・塩分・ 糖分の補給が必要であり, 治療が遅れれば生命にかかわる。その後も生涯にわたりグルココルチコイドと ミネラルコルチコイドの補充が必要である。新生児期・乳児期には食塩の補充も必要となる。 治療が軌道に乗った後も, 発熱などのストレスにさらされた際には副腎不全を起こして重篤な状態に陥ることがあるため, ストレス時にはグルココルチコイドの内服量を通常の2~3倍服用する。適切な治療が行わ れれば予後は比較的良好である。

予後
 副腎機能の回復は期待できないので, グルココルチコイドによる補充療法を生涯にわたって続けることにより症状もなく良好な一生を過ごすことができる。グルココルチコイドをストレス時に増量しなかったり, 服用を忘れたりするとショックを起こし, 生命の危険となる。適切な治療が行われれば予後は比較的良好であ る。

<診断基準>
部分的アジソン病を含めて対象とする。
1. 自覚症状
 ①色素沈着: あるいはまれに白班, 関節部, 手術創, 乳輪, 手掌の皮溝, 歯齦, 口腔粘膜, 舌, 口唇などに 特徴的。
 ②易疲労, 脱力感。
 ③体重減少
 ④消化器症状: 食欲不振, 悪心・ 嘔吐, 下痢, 腹痛
 ⑤精神症状: 無気力, 無関心, 不安感
 ⑥急性副腎皮質不全症状: 全身倦怠感, 頭痛, 悪心・ 嘔吐, 発熱などの非特異的症状に始まり, 急速に進行して意識障害, 呼吸困難, ショック
2 .他覚症状
①低血圧: 起立性低血圧症をきたしやすい。
②脱毛, 性腺機能低下: 女性では腋毛, 恥毛の脱落, 月経異常, 男性では性欲低下
③低血糖症状
3. 検査所見
 ①内分泌学的検査成績
  血漿コルチゾール低値と血漿 ACTH の高値を認め, 迅速 ACTH 負荷試験で血漿 コルチゾールの増加反応を認めなければ, 本症と診断できる。血漿コルチゾールは正常下限でも, ACTH 負荷に対して血漿コルチゾールの反応性が欠如, あるいは低下しているものを部分的アジソン病とよぶ。
 ②末梢血液像: 軽度の貧血や白血球数の減少および相対的リンパ球増加と好酸球増加。
 ③血清生化学
  アルドステロン欠乏による血清 Na, Cl の低下と K の上昇。血清 Na(mEq/l)/K(mEq/l)比が 30 以下(正常 は 32)。ときに高 Ca 血症, 代謝性アシドーシス, 水利尿の低下。
 ④免疫学的検査
  自己免疫機序の関与する特発性アジソン病では, 抗副腎抗体を検出することがある。

(Note)
Addison disease falls into the same category as pernicious anemia, systemic lupus erythematosus, myasthenia gravis, and Hashimoto thyroiditis, in which an autoimmune basis is suggested by some evidence and in which familial aggregation occurs. In all these conditions, the role of a single genetic locus in etiology is unclear. The isolated form of Addison disease is less frequent than that combined with other endocrinopathies, particularly hypoparathyroidism (see 240300). A noteworthy feature is the lack of hypoaldosteronism (Stempfel and Engel, 1960; Shepard et al., 1959). Androgen metabolism could not be tested. These cases may well have a defect limited to corticoid metabolism. Some of these cases may with more validity be classed as adrenal unresponsiveness to ACTH (202200, 300250).

Berlin (1952) reported Addison disease in brother and sister, the latter having also pernicious anemia. Brochner-Mortensen (1956) described Addison disease in 2 brothers and 2 of their maternal uncles. Meakin et al. (1959) described 2 brothers with onset of adrenal insufficiency at age 3 to 4 years.

Williams and Freeman (1965) reported adrenal cortical hypofunction without salt loss in 3 of 4 children of second-cousin parents. O'Donohoe and Holland (1968) described autopsy-proven adrenal hypoplasia in a sister of 2 affected males. Lemli and Smith (1968) reported affected sisters. The histologic findings differ in the X-linked (300200) and autosomal recessive forms of adrenal hypoplasia. In the former, the adrenal cortex shows disorganization with poor differentiation of cortical zones and presence of scattered clumps of eosinophilic cells. This is sometimes referred to as the cytomegalic type because of the large cells present as the only remaining cortical tissue. In the latter, there is absence or near-absence of both fetal and permanent cortex. This is sometimes called the 'miniature adult' type because the small adrenal cortex consists almost exclusively of permanent cortex. The latter type occurs either sporadically or as an autosomal recessive condition and may occur alone or, as is often the case, accompanied by anomalies of the brain and pituitary gland, as in anencephaly, or with pituitary gland abnormalities alone. Boyd and MacDonald (1960) reported marked hyperplasia of pituitary basophilic cells. Congenital hypoadrenocorticism may be misdiagnosed as 'sudden infant death syndrome.'

In the majority of cases, Addison disease is a component of an autoimmune polyendocrine syndrome, or APS (Gambelunghe et al., 1999). APS1 (240300), a rare disorder, is caused by mutation in the AIRE gene (607358), which resides on chromosome 21. APS2 (269200), more frequently found in adult patients, is a complex multigenic disease. The major histocompatibility complex class I chain-related MICA (600169) and MICB (602436) genes are located on chromosome 6 between the HLA-B (142830) and the B-associated transcript (see 142560) genes. The presence of 21-hydroxylase autoantibodies is a sensitive and specific marker of autoimmune Addison disease. Gambelunghe et al. (1999) evaluated the association of APS2-Addison disease with both MICA and MICB gene polymorphism 28 autoimmune (21-hydroxylase autoantibody-positive) Addison disease patients and in 75 healthy subjects from central Italy. They found evidence for a primary association of autoimmune Addison disease with the exon 5 microsatellite polymorphism of the MICA gene (MICA5.1). The MICA5.1 allele was significantly more frequent in Addison disease patients (79%) than in healthy subjects (36%) whereas MICA6 was significantly reduced in affected subjects. The A5.1/A5.1 genotype had an odds ratio for autoimmune Addison disease as high as 18.0 and an absolute risk of 1 per 1,131. In the presence of MICA5.1, MICB/CA-25 was significantly increased in Addison disease patients (15% vs 56%). The MICB/CA-17 allele was absent in Addison disease patients, but present in more than 25% healthy individuals. Among HLA-DR and -DQ haplotypes, only DRB1*03-DQA1*0501-DQB1*0201 (DR3/DQ2) was significantly more frequent in Addison disease patients than in healthy subjects, but only in the presence of MICA5.1. The authors concluded that susceptibility to autoimmune Addison disease is linked to the MICA microsatellite allele 5.1 and that both MICA5.1 and HLA-DR3/DQ2 are necessary to confer increased genetic risk for Addison disease.

Skinningsrud et al. (2008) presented evidence suggesting an association between autoimmune Addison disease and a 1858C-T SNP (rs2476601) in the PTPN22 gene (600716.0001) on chromosome 1p13. In a metaanalysis of 3 studies, including their own, comprising 563 European patients with the disorder, the authors found an odds ratio of 1.36 (p = 0.003) for carriers of the T allele.

(文献)
(1) Berlin R: Addison's disease. Familial incidence and occurrence in association with pernicious anemia. Acta Med Scand 144: 1-6, 1952
(2) Brochner-Mortensen IC: Familial occurrence of Addison's disease. Acta Med Scand 156: 205-209, 1956
(3) Meakin JW et al. Addison's disease in two brothers. J Clin Endocr Metab 19: 726-731, 1959
(4) Mitchell RG, Rhaney K: Congenital adrenal hypoplasia in siblings. Lancet I: 488-492, 1959
(5) Shepard TH et al. Familial Addison's disease: case reports of two sisters with corticoid deficiency unassociated with hypoaldosteronism. Am J Dis Child 97: 154-162, 1959
(6) Boyd JF, MacDonald AM: Adrenal cortical hypoplasia in siblings. Arch Dis Child 35: 561-568, 1960
(7) Stempfel RS Jr, Engel FL: A congenital, familial syndrome of adrenocortical insufficiency without hypoaldosteronism. J Pediat 57: 443-451, 1960
(8) Williams HE, Freeman M: Primary familial Addison's disease. Aust. Paediat J 1: 93-97, 1965
(9) Lemli L, Smith DW: Idiopathic adrenal insufficiency in two siblings. Maandschr. Kindergeneesk. 34: 63, 1968
(10) O'Donohoe NV, Holland PDJ: Familial congenital adrenal hypoplasia. Arch Dis Child 43: 717-723, 1968
(11) Gambelunghe G et al. Microsatellite polymorphism of the MHC class I chain-related (MIC-A and MIC-B) genes marks the risk for autoimmune Addison's disease. J. Clin. Endocr. Metab. 84: 3701-3707, 1999
(12) Skinningsrud, B.; Husebye, E. S.; Gervin, K.; Lovas, K.; Blomhoff, A.; Wolff, A. B.; Kemp, E. H.; Egeland, T.; Undlien, D. E. : Mutation screening of PTPN22: association of the 1858T-allele with Addison's disease. Europ. J. Hum. Genet. 16: 977-982, 2008

2009/03/05