Transcript PowerPoint - 埼玉医科大学総合医療センター 内分泌・糖尿病内科

Journal Club
Louiset E, Duparc C, Young J, Renouf S, Tetsi Nomigni M, Boutelet I, Libé R, Bram
Z, Groussin L, Caron P, Tabarin A, Grunenberger F, Christin-Maitre S, Bertagna X,
Kuhn JM, Anouar Y, Bertherat J, Lefebvre H.
Intraadrenal corticotropin in bilateral macronodular adrenal hyperplasia.
N Engl J Med. 2013 Nov 28;369(22):2115-25. doi: 10.1056/NEJMoa1215245.
Assié G, Libé R, Espiard S, Rizk-Rabin M, Guimier A, Luscap W, Barreau O,
Lefèvre L, Sibony M, Guignat L, Rodriguez S, Perlemoine K, René-Corail F,
Letourneur F, Trabulsi B, Poussier A, Chabbert-Buffet N, Borson-Chazot F,
Groussin L, Bertagna X, Stratakis CA, Ragazzon B, Bertherat J.
ARMC5 mutations in macronodular adrenal hyperplasia with Cushing's syndrome.
N Engl J Med. 2013 Nov 28;369(22):2105-14. doi: 10.1056/NEJMoa1304603.
2013年12月12日 8:30-8:55
８階 医局
埼玉医科大学 総合医療センター 内分泌・糖尿病内科
Department of Endocrinology and Diabetes,
Saitama Medical Center, Saitama Medical University
松田 昌文
Matsuda, Masafumi
Cushing症候群
These aberrant receptors include ectopic receptors
for glucose-dependent insulinotropic peptide,
luteinizing hormone, and catecholamines and
abnormally active eutopic receptors such as the
vasopressin type 1a and serotonin type 4 receptors.
The molecular defects that have been characterized
in samples of hyperplastic adrenals also include
activating mutations in the genes that encode the
corticotropin receptor, G-protein subunit αs, and
phosphodiesterase 11A, as well as the aberrant
expression of bioactive signals in the adrenocortical
cells, which leads to the formation of intraadrenal
regulatory loops.
INSERM Unité 982, Laboratory of Neuronal and Neuroendocrine Differentiation and Communication, Institute for
Research and Innovation in Biomedicine, and Rouen University, Mont-Saint-Aignan (E.L., C.D., S.R., M.T.N., I.B.,
Z.B., J-.M.K., Y.A., H.L.), the Department of Endocrinology, Hôpital Bicêtre, Assistance Publique–Hôpitaux de
Paris (AP-HP), University Paris Sud, INSERM Unité 693, Le Kremlin-Bicêtre (J.Y.), INSERM Unité 1016, Institut
Cochin (R.L., L.G., X.B., J.B.), the Department of Endocrinology AP-HP, Hôpital Cochin (L.G., X.B., J.B.),
Université Paris Descartes (L.G., X.B., J.B.), Centre National de la Recherche Scientifique Unité Mixte de
Recherche 8104 (L.G., X.B., J.B.), and the Department of Endocrinology, Hôpital Saint-Antoine, AP-HP (S.C.-M.),
Paris; the Department of Endocrinology and Metabolic Diseases, Centre Hospitalier Universitaire Larrey, Toulouse
(P.C.); the Department of Endocrinology, Hôpital Haut Lévêque, Centre Hospitalier Universitaire de Bordeaux,
Pessac (A.T.); Service de Médecine Interne et Nutrition, Centre Hospitalier Régional Universitaire de Strasbourg,
Strasbourg (F.G.); and the Department of Endocrinology, Diabetes, and Metabolic Diseases, Rouen University
Hospital, Rouen (J.M.K., H.L.) — all in France.
N Engl J Med. 2013 Nov 28;369(22):2115-25. doi: 10.1056/NEJMoa1215245.
Background
Bilateral macronodular adrenal hyperplasia is a
rare cause of primary adrenal Cushing's
syndrome. In this form of hyperplasia,
hypersecretion of cortisol suppresses the release
of corticotropin by pituitary corticotrophs, which
results in low plasma corticotropin levels. Thus,
the disease has been termed corticotropinindependent macronodular adrenal hyperplasia.
We examined the abnormal production of
corticotropin in these hyperplastic adrenal glands.
Methods
We obtained specimens of hyperplastic
macronodular adrenal tissue from 30 patients
with primary adrenal disease. The corticotropin
precursor proopiomelanocortin and corticotropin
expression were assessed by means of a
polymerase-chain-reaction assay and
immunohistochemical analysis. The production of
corticotropin and cortisol was assessed in 11
specimens with the use of incubated explants and
cell cultures coupled with hormone assays.
Corticotropin levels were measured in adrenal
and peripheral venous blood samples from 2
patients.
Pro-opiomelanocortin (POMC) is a precursor polypeptide with 241 amino
acid residues. POMC is synthesized from the 285-amino-acid-long
polypeptide precursor pre-pro-opiomelanocortin (pre-POMC), by the
removal of a 44-amino-acid-long signal peptide sequence during
translation.
• α-MSH produced by neurons in the arcuate nucleus has important roles in
the regulation of appetite and sexual behavior, while α-MSH secreted from
the intermediate lobe of the pituitary regulates the production of melanin.
• ACTH is a peptide hormone that regulates the secretion of glucocorticoids
from the adrenal cortex.
• β-Endorphin and [Met]enkephalin are endogenous opioid peptides with
widespread actions in the brain.
* PDE11A denotes the gene
encoding phosphodiesterase 11A,
and GNAS the gene encoding the
G-protein subunit αS (GSα).
† Messenger RNA (mRNA)
expression levels for POMC, the
gene encoding
proopiomelanocortin, which were
measured with the use of realtime reverse-transcriptase–
polymerase-chain-reaction assays,
have been expressed as
picograms per nanogram of
cyclophilin.
‡ Data have previously been
reported for 20 of the patients
Figure 2. Immunohistologic Characterization of Corticotropin- Producing Cells in Hyperplastic Adrenal Samples from Patients with Associated
Cushing’s Syndrome. Immunohistochemical labeling of consecutive sections of hyperplastic tissue reveals antibodies against corticotropin
(Panels A, C, E, G, I, and K), chromogranin A (CGA) (Panel B), CD45 (Panel D), and T-box factor, pituitary (TPIT) (Panel F), as well as
antibodies against markers of steroidogenic differentiation, including steroidogenic factor 1 (SF-1) (Panel H), scavenger-receptor class B type 1
(SR-B1) (Panel J), and 17α-hydroxylase (17-OH) (Panel L). Black arrows denote cells that are positive for corticotropin, and open arrows cells
that are positive for CGA (Panel B) or CD45 (Panel D). Immunostaining was revealed with the use of diaminobenzidine (brown) or permanent red
(pink). Patient numbers are indicated as P1, P2, and so on. Scale bars represent 50 μm.
C: Schematic representation of the putative regulatory mechanisms involved in
the control of cortisol secretion by adrenal macronodular hyperplastic glands.
Adrenal corticotropin-producing cells express functional aberrant receptors such as
serotonin type 4 (5-HT4) and 7 (5-HT7), luteinizing hormone (LH-R) and glucosedependent insulinotropic peptide (GIP-R) receptors. Activation of these receptors by
their natural ligands both stimulates cortisol release and induces the release of
corticotropin which in turns triggers cortisol production by adrenocortical cells through
autocrine and paracrine mechanisms involving the melanocortin type 2 receptor (MC2R).
SRBI, scavenger receptor B1; SgII, secretogranin II; PKA, protein kinase A.
N, Normal value; CI, contraindicated; ND, Not determined; NS, Not significant (Plasma cortisol response<25%); 5HT4-R, serotonin type 4 receptor.
Results
The expression of proopiomelanocortin messenger RNA
(mRNA) was detected in all samples of hyperplastic adrenal
tissue. Corticotropin was detected in steroidogenic cells
arranged in clusters that were disseminated throughout the
adrenal specimens. Adrenal corticotropin levels were higher
in adrenal venous blood samples than in peripheral venous
samples, a finding that was consistent with local production
of the peptide within the hyperplastic adrenals. The release
of adrenal corticotropin was stimulated by ligands of aberrant
membrane receptors but not by corticotropin-releasing
hormone or dexamethasone. A semiquantitative score for
corticotropin immunostaining in the samples correlated with
basal plasma cortisol levels. Corticotropin-receptor
antagonists significantly inhibited in vitro cortisol secretion.
Conclusions
Cortisol secretion by the adrenals in patients with
macronodular hyperplasia and Cushing's
syndrome appears to be regulated by
corticotropin, which is produced by a
subpopulation of steroidogenic cells in the
hyperplastic adrenals. Thus, the hypercortisolism
associated with bilateral macronodular adrenal
hyperplasia appears to be corticotropindependent.
(Funded by the Agence Nationale de la Recherche and others.)
Message
原発性の副腎疾患患者30人から採取した大結節
性副腎過形成組織を対象に、コルチコトロピン
の異常産生を調査。副腎コルチコトロピンは末
梢静脈血検体よりも副腎静脈血検体で値が高く、
その放出は異常な膜受容体のリガンドに刺激さ
れていた。検体のコルチコトロピン免疫染色の
半定量的スコアは、基礎血漿コルチゾール値と
相関していた。
ところで、このような患者でGIPに反応する患者にはDPP-4阻害薬
は使ってはいけないだろう。
armadillo repeat containing 5
the function of ARMC5 is unknown. It encodes a protein that contains an
armadillo repeat domain, suggesting that protein–protein interactions may be
important for its function. β-catenin, which also contains armadillo repeats, is
another gene that is frequently mutated in various cancers, including
adrenocortical tumors
This observation suggests that ARMC5 might be a tumor-suppressor gene that
leads to the development of a tumor when a primary inactivating alteration on
one allele in the germline is present and a somatic secondary event affecting the
second allele occurs.
INSERM Unité 1016, Centre National de la Recherche Scientifique Unité Mixte de Recherche 8104, Institut Cochin (G.A., R.L., S.E.,
M.R.-R., A.G., W.L., O.B., L.L., S.R., K.P., F.R.-C., F.L., L. Groussin, X.B., B.R., J.B.), Faculté de Médecine Paris Descartes,
Université Paris Descartes, Sorbonne Paris Cité (G.A., S.E., A.G., O.B., L.L., M.S., K.P., F.R.-C., L. Groussin, X.B., J.B.), Department
of Endocrinology, Referral Center for Rare Adrenal Diseases (G.A., R.L., O.B., L. Guignat, L. Groussin, X.B., J.B.), and Department
of Pathology (M.S.), Assistance Publique–Hôpitaux de Paris, Hôpital Cochin, and Unit of Endocrinology, Department of Obstetrics
and Gynecology, Hôpital Tenon (N.C.-B.) — all in Paris; Unit of Endocrinology, Centre Hospitalier du Centre Bretagne, Site de Kério,
Noyal-Pontivy (B.T.), Unit of Endocrinology, Hôtel Dieu du Creusot, Le Creusot (A.P.), and Department of Endocrinology Lyon-Est,
Groupement Hospitalier Est, Bron (F.B.-C.) — all in France; and the Section on Endocrinology and Genetics, Program on
Developmental Endocrinology and Genetics and the Pediatric Endocrinology Inter-Institute Training Program, Eunice Kennedy
Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD (C.A.S.).
N Engl J Med. 2013 Nov 28;369(22):2105-14. doi: 10.1056/NEJMoa1304603.
Background
Corticotropin-independent
macronodular adrenal hyperplasia may
be an incidental finding or it may be
identified during evaluation for
Cushing's syndrome. Reports of familial
cases and the involvement of both
adrenal glands suggest a genetic origin
of this condition.
Methods
We genotyped blood and tumor DNA
obtained from 33 patients with corticotropinindependent macronodular adrenal
hyperplasia (12 men and 21 women who
were 30 to 73 years of age), using singlenucleotide polymorphism arrays,
microsatellite markers, and whole-genome
and Sanger sequencing. The effects of
armadillo repeat containing 5 (ARMC5)
inactivation and overexpression were tested
in cell-culture models.
Results
The most frequent somatic chromosome alteration was loss
of heterozygosity at 16p (in 8 of 33 patients for whom data
were available [24%]). The most frequent mutation identified
by means of whole-genome sequencing was in ARMC5,
located at 16p11.2. ARMC5 mutations were detected in
tumors obtained from 18 of 33 patients (55%). In all cases,
both alleles of ARMC5 carried mutations: one germline and
the other somatic. In 4 patients with a germline ARMC5
mutation, different nodules from the affected adrenals
harbored different secondary ARMC5 alterations.
Transcriptome-based classification of corticotropinindependent macronodular adrenal hyperplasia indicated
that ARMC5 mutations influenced gene expression, since all
cases with mutations clustered together. ARMC5 inactivation
decreased steroidogenesis in vitro, and its overexpression
altered cell survival.
Conclusions
Some cases of corticotropin-independent
macronodular adrenal hyperplasia appear
to be genetic, most often with inactivating
mutations of ARMC5, a putative tumorsuppressor gene. Genetic testing for this
condition, which often has a long and
insidious prediagnostic course, might result
in earlier identification and better
management.
(Funded by Agence Nationale de la Recherche and others.)
Approximately 20% of cases — mainly cortisol-secreting unilateral adenomas or
carcinomas — are considered corticotropin-independent. Cushing’s syndrome rarely (in
<2% of cases) results from primary bilateral nodular hyperplasia (either corticotropinindependent macronodular adrenal hyperplasia or micronodular hyperplasia). Bilateral
macronodular adrenal hyperplasia with subclinical cortisol secretion is more frequent;
approximately 10% of incidentally detected adrenal lesions, which are seen in
approximately 4% of adults, are bilateral.
“Corticotropin-independent macronodular adrenal hyperplasia” now seems
inappropriate as a term, and this disease should be termed primary bilateral
macronodular adrenal hyperplasia; in contrast, secondary bilateral macronodular
adrenal hyperplasia can occur after long-term adrenal stimulation by corticotropin
in Cushing’s disease or ectopic corticotropin syndromes.
Message
コルチコトロピン非依存性副腎皮質大結節性過形成
を呈する患者33人を対象に、遺伝子配列解析で変異
を同定。最も頻度が高かったのは、腫瘍で検出され
たARMC5（armadillo repeat containing 5）の変異
だった（55％）。トランスクリプトームに基づく分
類から、ARMC5変異が遺伝子発現に影響を及ぼすこ
とが示された。