佐久間 一基

Context: Necrolytic migratory erythema (NME) occurs in approximately 70% of patients with glucagonoma syndrome. Excessive stimulation of metabolic pathways by hyperglucagonemia, which leads to hypoaminoacidemia, contributes to NME pathogenesis. However, the molecular pathogenesis of glucagonoma and relationships between metabolic abnormalities and clinical symptoms remain unclear. Patient: A 53-year-old woman was referred to our hospital with a generalized rash and weight loss. NME was diagnosed by histopathological examination of skin biopsy tissue. Laboratory tests revealed diabetes, hyperglucagonemia, marked insulin resistance, severe hypoaminoacidemia, ketosis, and anemia. Enhanced computed tomography scans detected a 29-mm pancreatic hypervascular tumor, which was eventually diagnosed as glucagonoma. Preoperative treatment with octreotide long-acting release reduced the glucagon level, improved the amino acid profile, and produced NME remission. Surgical tumor excision normalized the metabolic status and led to remission of symptoms, including NME. Interventions: Whole-exome sequencing (WES) and subsequent targeted capture sequencing, followed by Sanger sequencing and pyrosequencing, identified biallelic alteration of death-domain associated protein (DAXX) with a combination of loss of heterozygosity and frameshift mutations (c.553_554del:p.R185fs and c.1884dupC:p.C629fs) in the glucagonoma. Consistently, immunohistochemistry confirmed near-absence of DAXX staining in the tumor cells. Tumor expression of glucagon and somatostatin receptor subtype 2 and 3 messenger RNA was markedly upregulated. Conclusions: This is a report of glucagonoma with biallelic inactivation of DAXX determined by WES. The tumor manifested as glucagonoma syndrome with generalized NME. This case showed the relationship between hypoaminoacidemia and NME status. Further investigations are required to elucidate the underlying mechanisms of NME onset and glucagonoma tumorigenesis.

We herein report the case of a 25-year-old woman who presented with severe headache and visual field defects after childbirth. Magnetic resonance imaging revealed marked swelling of the pituitary gland, and an endocrinological examination revealed panhypopituitarism and diabetes insipidus. An immunohistological analysis of a transsphenoidal biopsy sample of the pituitary gland showed the significant accumulation of an immunogloblin G4 (IgG4)-positive population, leading to the diagnosis of IgG4-related hypophysitis. The patient was treated with prednisolone, which markedly reduced the swelling of the pituitary gland, in association with recovery of the pituitary function. This is a rare case of biopsy-proven IgG4-related hypophysitis with a postpartum onset.

Objective: Familial dysalbuminemic hyperthyroxinemia (FDH) is caused by abnormal human serum albumin (HSA) with an increased thyroxine (T4) affinity leading to euthyroid hyperthyroxinemia. One-and 2-step immunoassays of serum samples from FDH patients (e.g., Japanese patients) with the HSA R218P mutation can yield false-positive free thyroxine (FT4) results. Therefore, it is difficult to distinguish FDH from syndrome of inappropriate secretion of thyroid-stimulating hormone (TSH) (e.g., syndrome of resistance to thyroid hormone, TSH-producing pituitary adenoma), even when multiple assays are used. To investigate T4 to HSA binding, we examined serum samples from 7 patients from 3 Japanese families with FDH. Clinically, abnormal thyroid function tests were noted in pregnant Patient 1. Patients 2 and 3 had histories of inappropriate treatment with antithyroid drugs and surgery. Methods: All patients and affected family members were diagnosed with FDH using direct sequencing analysis. Gel filtration high-performance liquid chromatography was used for the biochemical analyses. Results: The genomic analysis revealed a heterozygous missense mutation in HSA (R218P). In FDH patient sera, the albumin effluent corresponded to the peaks for total T4 (TT4); approximately 60% of the T4 in the effluent was detected as FT4. The results for the albumin effluent from healthy volunteer and TSHoma patient sera showed no corresponding TT4 peak. Conclusion: In the FDH patients, a relatively larger quantity of T4 was bound to abnormal HSA. This bound T4 was measured as FT4 during the analysis.

Background: A functional pituitary adenoma can produce multiple anterior-pituitary hormones, such as growth hormone (GH) producing adenomas (GHoma) with prolactin or thyrotropin stimulating hormone production in the same lineage. However, it is very rare that acromegaly shows subclinical Cushing's disease (SCD) beyond the lineage. Here we describe the involvement of intratumoral coexistence with 2 types of hormone-producing cells associated with different lineage in acromegaly concomitant with SCD. Case presentation: In our study, we performed clinical evaluation of the patient showing acromegaly with SCD. To elucidate the mechanisms of this pathology, we analyzed immunohistochemistry and gene expression of anterior-pituitary hormones and transcriptional factors in the resected pituitary tumor. On immunohistochemical staining, most of the tumor cells were strongly stained for GH antibody, while some cells were strongly positive for adrenocorticotropic hormone (ACTH). Gene expression analysis of a transsphenoidal surgery sample of the pituitary gland revealed that ACTH-related genes, such as POMC, Tpit, and NeuroD1 mRNA, had higher expression in the tumor tissue than the nonfunctional adenoma but lower expression compared to an adenoma of typical Cushing's disease. Further, double-labeling detection methods with a fluorescent stain for ACTH and GH demonstrated the coexistence of ACTH-positive cells (GH-negative) among the GH-positive cells in the tumor. Additionally, Pit-1 expression was reduced in the ACTH-positive cells from tumor tissue primary culture. Conclusion: Here we described a case of a pituitary tumor diagnosed with acromegaly associated with SCD. We performed quantitative-expression analyses of transcriptional factors of the tumor tissue and immunohistochemistry analysis of tumor-derived primary culture cells, which suggested that the multihormonal pituitary adenoma concomitant with Pit-1 and Tpit lineage cells caused acromegaly associated with SCD.

Context: Pheochromocytoma is a catecholamine-producing tumor that originates from adrenal chromaffin cells and is capable of secreting various hormones, including ACTH. Case Description: A 56-year-old female presented with Cushingoid appearance and diabetic ketoacidosis. Endocrinological examinations demonstrated ectopic ACTH production with hypercortisolemia and excess urinary cortisol accompanied by elevated plasma and urine catecholamines. Computed tomography revealed a large left adrenal tumor with bilateral adrenal enlargement. Metaiodobenzylguanidine scintigraphy revealed abnormal accumulation in the tumor, which was eventually diagnosed as pheochromocytoma with ectopic ACTH secretion with subsequent manifestation of Cushing's syndrome. Ectopic ACTH secretion and catecholamine production were blocked by metyrapone treatment, whereas dexamethasone paradoxically increased ACTH secretion. Left adrenalectomy resulted in complete remission of Cushing's syndrome and pheochromocytoma. In Vitro Studies: Immunohistological analysis revealed that the tumor contained two functionally distinct chromaffin-like cell types. The majority of tumor cells stained positive for tyrosine hydroxylase (TH), whereas a minor population of ACTH-positive tumor cells was negative for TH. Furthermore, gene expression and in vitro functional analyses using primary tumor tissue cultures demonstrated that dexamethasone facilitated ACTH as well as catecholamine secretion with parallel induction of proopiomelanocortin (POMC), TH, and phenylethanolamine N-methyltransferase mRNA, supporting a glucocorticoid-dependent positive-feedback loop of ACTH secretion in vivo. DNA methylation analysis revealed that the POMC promoter of this tumor, particularly the E2F binding site, was hypomethylated. Conclusion: We present a case of ectopic ACTH syndrome associated with pheochromocytoma. ACTH up-regulation with paradoxical response to glucocorticoid, possibly through the hypomethylation of the POMC promoter, exacerbated the patient's condition.

Objective: Primary macronodular adrenal hyperplasia (PMAH) is considered a predominantly sporadic disease, but familial forms are well recognized. Genetic studies revealed germline mutations in the armadillo repeat containing 5 gene (ARMC5) in the majority of PMAH cases. Furthermore, somatic ARMC5 mutations, as different types of second-hit mutations and loss of heterozygosity have been reported in each adrenal nodule in PMAH. Here, we describe the involvement of ARMC5 alteration in a familial case of PMAH. Methods: In our study, we performed clinical and genetic evaluations in a mother and her son with familial PMAH. To search for mutations and deletion of ARMC5, we used Sanger sequencing and droplet digital polymerase chain reaction (ddPCR), respectively. Results: Both patients showed the same phenotype of subclinical Cushing syndrome, with mild excess of mineralocorticoids and vasopressin-responsive cortisol secretion. The ddPCR analysis demonstrated that both mother and son had germline deletions in exons 1 to 5 of the ARMC5 gene locus. Furthermore, Sanger sequencing of DNA from the right and left adrenal nodules as well as peripheral blood of the son revealed the presence of another germline, missense mutation in ARMC5 exon 3 (p.P347S). Conclusion: This is the first report demonstrating germline deletion of ARMC5 in familial PMAH. In addition to investigating mutations, germline and somatic deletions of ARMC5 could be examined by ddPCR, which permits rapid and accurate evaluation of the ARMC5 allelic status.

OBJECTIVE: We report a 44-year old man with ectopic adrenocorticotropic hormone (ACTH) syndrome caused by bronchial carcinoid that developed Cushing syndrome. METHODS: We performed several imaging studies, including chest and abdominal CT, for exploration of nodules and selective pulmonary arterial sampling for localizing a source of ectopic ACTH production. RESULTS: The patient was diagnosed as Cushing syndrome due to ectopic production of ACTH without identification of its source(s). After 2 years' follow-up with repeated CT scans every 6-12 months and treatment with metyrapone, chest CT revealed two small nodules respectively in the segment (S) 4 and 10 of the right lung. We performed selective pulmonary arterial sampling from branches of the right pulmonary artery to obtain blood from the nodules in a reverse flow fashion: wedged sampling from the basal branch (A8, 9 and 10) revealed significant elevation of ACTH, whereas sampling from the lateral branch (A4) did not, indicating that the S10 nodule produced ACTH ectopically. The video-assisted thoracoscopic surgery removing the right inferior lobe normalized plasma ACTH, serum cortisol and 24-hour urinary free cortisol. The S10 nodule was histologically diagnosed as atypical bronchial carcinoid containing immunoreactive ACTH. CONCLUSIONS: Selective pulmonary arterial sampling was useful for localizing the lesion of ectopic ACTH production and helped make the decision for its surgical removal. This procedure should be considered once lung nodules suspicious for ectopic ACTH production are identified in patients with EAS.

We analyzed the expression profiles of several steroidogenic enzymes in normal adrenals, aldosterone-producing adenomas (APA), cortisol-producing adenomas combined with Cushing's syndrome (CPA) or with subclinical Cushing's syndrome (SCPA), and nonfunctioning adrenal adenomas (NFA) to clarify the nature and characteristics of steroidogenesis in APA. Clinical data were collected for all subjects. In resected adrenal glands (normal adrenals, APA, CPA, SCPA, and NFA), the mRNA expression levels of the CYP17, HSD3B2, CYP11B1, and CYP11B2 genes were studied using real-time quantitative PCR and immunohistochemistry. The CYP11B2 mRNA level in APA was significantly higher than that in other groups. The CYP17/HSD3B2 ratio for mRNA in APA was significantly lower than those in the other groups. Low ratio of CYP17/HSD3B2 with high expression of CYP11B2 seems to explain steroidogenic characteristics of APA.

67歳男。40歳時から高血圧症、脂質異常症、高尿酸血症に対し、近医で内服加療されていた。2007年、低カリウム血症、下腿浮腫が出現し、内服治療を開始したが改善しなかった。その後、動悸、こむら返りが頻繁に出現するようになり、2009年末に低カリウム血症精査目的で紹介となった。血性レニン活性(PRA)、血中アルドステロン濃度(PAC)の低値を認め、偽性アルドステロン症を疑った。外来での病歴聴取では甘草、グリチルリチンを含有する漢方薬の摂取歴はなかった。入院後、詳細な問診を行った結果、2007年2月から健康食品の新五浄心を目安の約10倍近く、継続して摂取していることが判明した。新五浄心を中止し、カリウム製剤の補充を継続した結果、低カリウム血症は改善した。臨床症状も改善し、PRA、PACは上昇し、代謝性アルカローシスも消失したため、新五浄心による偽性アルドステロン症と診断した。

Obstruction of the left ventricular outflow tract (LVOT) is usually complicated by hypertrophic cardiomyopathy or left ventricular hypertrophy. It occurs rarely in cases of sigmoid-shaped septum (SS), which are considered as a normal part of the aging process. The 2 cases of SS with obstruction of the LVOT were observed. Their complaints were dyspnea on effort and exercise increased the left ventricular pressure gradient. In both cases, atenolol administration decreased rest pressure gradient. Moreover, additional cibenzoline administration decreased the pressure gradient caused by exercise. It is emphasized that dual therapy with cibenzoline and atenolol is effective in resolving the obstruction of the LVOT caused by SS. (Circ J 2008; 72: 2087-2091)