Ryusaku Matsumoto

The prevalence of IgG4-related hypophysitis in 170 consecutive patients with hypopituitarism and/or central diabetes insipidus and review of the literature

OBJECTIVE The prevalence and clinical characteristics of IgG4-related hypophysitis remain unclear due to the limited number of case reports. Therefore, in this study, we screened consecutive outpatients with hypopituitarism and/or diabetes insipidus (DI) to estimate its prevalence. METHODS A total of 170 consecutive outpatients with hypopituitarism and/or central DI were screened at Kobe University Hospital for detecting IgG4-related hypophysitis by pituitary magnetic resonance imaging, measuring serum IgG4 concentrations, assessing the involvement of other organs, and carrying out an immunohistochemical analysis to detect IgG4-positive cell infiltration. RESULTS Among the screened cases, 116 cases were excluded due to diagnosis of other causes such as tumors and congenital abnormalities. Additionally, 22 cases with isolated ACTH deficiency were analyzed and were found not to meet the criteria of IgG4-related hypophysitis. The remaining 32 cases were screened and seven were diagnosed with IgG4-related hypophysitis, of which three cases were diagnosed by analyzing pituitary specimens. IgG4-related hypophysitis was detected in 30% (seven of 23 patients) of hypophysitis cases and 4% of all hypopituitarism/DI cases. The mean age at the onset of IgG4-related hypophysitis was 61.8±8.8 years, and the serum IgG4 concentration was 191.1±78.3 mg/dl (normal values 5-105 mg/dl and values in IgG4-related disease (RD) ≥135 mg/dl). Pituitary gland and/or stalk swelling was observed in six patients, and an empty sella was observed in one patient. Multiple co-existing organ involvement was observed in four of the seven patients prior to the onset of IgG4-related hypophysitis. CONCLUSION These data suggest that the prevalence of IgG4-related hypophysitis has been underestimated. We should also consider the possibility of the development of hypopituitarism/DI caused by IgG4-related hypophysitis during the clinical course of other IgG4-RDs.

IGF-I induces senescence of hepatic stellate cells and limits fibrosis in a p53-dependent manner

Hepatic fibrosis in nonalcoholic steatohepatitis (NASH) and cirrhosis determines patient prognosis; however, effective treatment for fibrosis has not been established. Oxidative stress and inflammation activate hepatic stellate cells (HSCs) and promote fibrosis. In contrast, cellular senescence inhibits HSCs’ activity and limits fibrosis. The aim of this study was to explore the effect of IGF-I on NASH and cirrhotic models and to clarify the underlying mechanisms. We demonstrate that IGF-I significantly ameliorated steatosis, inflammation, and fibrosis in a NASH model, methionine-choline-deficient diet-fed db/db mice and ameliorated fibrosis in cirrhotic model, dimethylnitrosamine-treated mice. As the underlying mechanisms, IGF-I improved oxidative stress and mitochondrial function in the liver. In addition, IGF-I receptor was strongly expressed in HSCs and IGF-I induced cellular senescence in HSCs in vitro and in vivo. Furthermore, in mice lacking the key senescence regulator p53, IGF-I did not induce cellular senescence in HSCs or show any effects on fibrosis. Taken together, these results indicate that IGF-I induces senescence of HSCs, inactivates these cells and limits fibrosis in a p53-dependent manner and that IGF-I may be applied to treat NASH and cirrhosis.

Long-term effects of growth hormone replacement therapy on liver function in adult patients with growth hormone deficiency

OBJECTIVE Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are frequently observed in patients with adult growth hormone deficiency (AGHD) and short-term GH replacement therapy (GHRT) has reportedly been efficacious in NAFLD and NASH. The aim of this study was to investigate whether long-term GHRT is an effective treatment for the hepatic comorbidities in AGHD. DESIGN This is a retrospective observational study. We recruited 54 consecutive hypopituitary patients with AGHD. Among them, 31 patients who had received GHRT for more than 24 months were compared with 19 age- and sex-matched patients without GHRT. We also analyzed the long term effect of GHRT on 14 patients diagnosed with NASH by liver biopsy. In addition, we subdivided the GHRT group into GH-responder and GH-non-responder groups and analyzed the factors associated with the efficacy of the treatment. RESULTS For a period of 24 months, the significant reduction of serum liver enzyme levels and a fibrotic marker was observed in patients receiving GHRT compared with the control group. Furthermore, GHRT also improved liver enzyme levels in AGHD patients with NASH. The GH-non-responder group showed a higher proportion of patients who gained weight during the study period. CONCLUSIONS These results indicate that GHRT is efficacious for improving serum liver enzyme levels for at least 24 months in patients with AGHD. To optimize this effect, it is important to avoid body weight gain during the treatment.

Involvement of PIT-1-Reactive Cytotoxic T Lymphocytes in Anti-PIT-1 Antibody Syndrome

CONTEXT Anti-pituitary-specific transcriptional factor 1 (PIT-1) antibody syndrome is characterized by acquired growth hormone (GH), prolactin (PRL), and thyroid-stimulating hormone (TSH) deficiencies associated with circulating anti-PIT-1 antibodies. Although autoimmunity to PIT-1 has been suggested as a pathogenesis, the precise mechanism of the syndrome remains unclarified. OBJECTIVE To elucidate the involvement of antibody- or cell-mediated immunity in anti-PIT-1 antibody syndrome. MATERIALS AND METHODS To investigate a direct effect of anti-PIT-1 antibody on pituitary cells, cell proliferation, and cytotoxicity detection assays were performed using patient serum. Enzyme-linked immunospot (ELISpot) assay was performed to evaluate the involvement of PIT-1-reactive cytotoxic T lymphocytes (CTLs). An immunohistochemical analysis using anti-CD4 or anti-CD8 antibody was performed to examine tissue infiltration by CTLs. RESULTS Patient serum did not exhibit any inhibitory effect on cell proliferation and secretion of GH and PRL in GH3 cells. In addition, complement-dependent cytotoxicity was not detected in patient serum on GH3 cells or primary pituitary cells. The ELISpot assay revealed the presence of CTLs that specifically reacted to the recombinant PIT-1 protein in the patients peripheral lymphocytes. CD8(+) cell infiltrations, which is the characteristic of CTLs, were observed in the pituitary gland, adrenal gland, stomach, thyroid gland, liver, and pancreas of the patient with anti-PIT-1 antibody syndrome. CONCLUSIONS These results suggest that the anti-PIT-1 antibody is not a cause but a marker of anti-PIT-1 antibody syndrome, in which CTLs play a pivotal role in the pathogenesis.

Accelerated Telomere Shortening in Acromegaly; IGF-I Induces Telomere Shortening and Cellular Senescence

Objective Patients with acromegaly exhibit reduced life expectancy and increased prevalence of age-related diseases, such as diabetes, hypertension, and cardiovascular disease. However, the underlying mechanism has not been fully elucidated. Telomere shortening is reportedly associated with reduced life expectancy and increased prevalence of these age-related diseases. Methods We measured telomere length in patients with acromegaly using quantitative PCR method. The effect of GH and IGF-I on telomere length and cellular senescence was examined in human skin fibroblasts. Results Patients with acromegaly exhibited shorter telomere length than age-, sex-, smoking-, and diabetes-matched control patients with non-functioning pituitary adenoma (0.62 ± 0.23 vs. 0.75 ± 0.35, respectively, P = 0.047). In addition, telomere length in acromegaly was negatively correlated with the disease duration (R 2 = 0.210, P = 0.003). In vitro analysis revealed that not GH but IGF-I induced telomere shortening in human skin fibroblasts. Furthermore, IGF-I-treated cells showed increased senescence-associated β-galactosidase activity and expression of p53 and p21 protein. IGF-I-treated cells reached the Hayflick limit earlier than GH- or vehicle-treated cells, indicating that IGF-I induces cellular senescence. Conclusion Shortened telomeres in acromegaly and cellular senescence induced by IGF-I can explain, in part, the underlying mechanisms by which acromegaly exhibits an increased morbidity and mortality in association with the excess secretion of IGF-I.

The prevalence of acromegaly in hospitalized patients with type 2 diabetes.

The prevalence of acromegaly is estimated to be 8-24/100,000, but several recent studies suggest it is underestimated. In particular, acromegaly is considered more prevalent in patients with type 2 diabetes mellitus (T2DM) than in the normal population. This study aimed to evaluate the prevalence of acromegaly in hospitalized patients with T2DM. A total of 327 hospitalized patients with T2DM were recruited as subjects. If serum insulin-like growth factor 1 (IGF-1) levels were found to be elevated, random GH level was measured or oral glucose tolerance test (OGTT) was performed. Five patients with elevated serum IGF-1 levels and random GH level or inadequate suppression of GH in the OGTT underwent pituitary magnetic resonance imaging. Of those patients, pituitary adenoma was detected in 2 patients. These 2 patients were diagnosed with acromegaly, as they also exhibited mild acromegalic features. Intriguingly, both these patients exhibited severe macroangiopathy and an absence of microangiopathy. The prevalence of acromegaly in the hospitalized patients with T2DM in this study was therefore 0.6%, suggesting a higher prevalence than that predicted. Although a large-scale prospective study is required to clarify the precise prevalence of acromegaly in hospitalized patients with T2DM, the present study shows that it is useful to screen hospitalized patients with T2DM for acromegaly by measuring their serum IGF-1 level.

A novel thymoma-associated autoimmune disease: Anti-PIT-1 antibody syndrome

Anti-PIT-1 antibody syndrome has recently been reported and characterized by acquired growth hormone (GH), prolactin (PRL), and thyroid-stimulating hormone (TSH) deficiencies associated with autoimmunity to a pituitary specific transcription factor PIT-1, which plays an essential role in GH-, PRL-, and TSH-producing cells. Although circulating anti-PIT-1 antibody and PIT-1-reactive cytotoxic T cells (CTLs) were detected in the patients, the pathophysiology and precise mechanisms for the autoimmunity remain unclarified. During the follow up, thymoma was diagnosed in all 3 cases with anti-PIT-1 antibody syndrome. Immunohistochemical analysis revealed that PIT-1 was strongly expressed in neoplastic cortical thymic epithelial cells. Importantly, after thymectomy, the titer of anti-PIT-1 antibody decreased and reactivity of CTLs toward PIT-1 diminished. These data strongly suggest that the aberrant expression of PIT-1 in the thymoma plays a causal role in the development of this syndrome. Thus, we define that this syndrome is a novel thymoma-associated autoimmune disease.

Prevalence of Simple Renal Cysts in Acromegaly.

Objective Various organs are known to be affected by the comorbidities of acromegaly. However, the involvement of renal structural comorbidities, such as cysts, has so far remained largely unknown. In this single-center study, we aimed to determine the prevalence and factors associated with simple renal cysts in Japanese patients with acromegaly. Methods A total of 71 consecutive patients with acromegaly were analyzed, who all underwent abdominal ultrasonography at diagnosis between 1986 and 2012 at Kobe University Hospital. Results Of these 71 patients, 23 (32.4%) exhibited simple renal cysts. Acromegalic patients with renal cysts tended to be significantly older, had a higher prevalence of smoking- and higher nadir growth hormone (GH) levels during the oral glucose tolerance test (OGTT) than did those without renal cysts. A multivariate logistic regression analysis showed age, smoking, and nadir GH to be independent factors associated with renal cysts. Interestingly, the number of renal cysts positively correlated with both the basal GH levels and nadir GH levels during OGTT (r=0.66, p<0.05 and r=0.70, p<0.05, respectively). In addition, the mean diameter of renal cysts positively correlated with the systolic blood pressure (r=0.84, p<0.005). Conclusion This is the first report to show the prevalence of simple renal cysts in patients with acromegaly. Elevated nadir GH levels during OGTT were found to be associated with an increased risk of simple renal cysts. Therefore, an excessive secretion of GH may be related to the development of renal cysts.

Hypercalcemic crisis resulting from near drowning in an indoor public bath

Patient: Male, 66 Final Diagnosis: Hypercalcemic crisis Symptoms: Near drowning state Medication: — Clinical Procedure: — Specialty: Critical care medicine Objective: Challenging differential diagnosis Background: Hypercalcemic crisis, generally caused by malignancy or primary hyperparathyroidism, is a life-threatening emergency that can result in multi-organ failure. Lowering the patient’s calcium level immediately and determining the correct etiology are essential. Case Report: We report a case of hypercalcemic crisis with a novel etiology. A 66-year-old male presented to the emergency room in cardiac arrest with a ventricular arrhythmia after being discovered submerged in an indoor public bath. He underwent cardioversion and was emergently intubated. Computed tomography showed bilateral pulmonary edema, suspected from water aspiration. Laboratory data revealed severe hypercalcemia and mild hypernatremia. Following three days of continuous hemodiafiltration, serum Ca decreased to and remained within normal limits. We concluded the etiology of hypercalcemia was absorption of Ca resulting from aspirated water. Conclusions: Near drowning can be a cause of hypercalcemic crisis. For cases of near drowning, it is important to investigate the source of the aspirated water and consider electrolyte abnormalities in the diagnosis.

Two Cases of Atezolizumab-Induced Hypophysitis

Cancer immunotherapy has emerged as treatment of multiple advanced cancer types. Immune checkpoint inhibitors, namely anticytotoxic T-lymphocyte antigen-4 (CTLA-4), antiprogrammed cell death-1 (PD-1), and antiprogrammed cell death-1 ligand 1 (PD-L1) antibodies, have been used for treatment of various cancers. Classified as immune-related adverse events, several endocrinopathies, including hypophysitis, are associated with these agents. Although anti-CTLA-4–induced hypophysitis has been frequently observed, hypophysitis upon use of anti-PD-1 and anti-PD-L1 antibodies is rare. Case 1 is a 65-year-old man presented with a stage IV non-small cell lung cancer (NSCLC) treated with atezolizumab (an anti-PD-L1 antibody) following several inefficacious chemotherapies. After 56 weeks of the treatment, he complained of general malaise and appetite loss, and was diagnosed with adrenal insufficiency. Endocrinological examination revealed isolated adrenocorticotropic hormone (ACTH) deficiency; pituitary magnetic resonance imaging (MRI) showed anterior pituitary atrophy. Hydrocortisone replacement therapy rapidly improved his symptoms and enabled him to continue atezolizumab therapy. Case 2 is a 70-year-old man with a stage IV NSCLC treated with atezolizumab. After 52 weeks of treatment, he was diagnosed with isolated ACTH deficiency. Pituitary MRI revealed no obvious abnormalities in the anterior pituitary. Hydrocortisone replacement therapy was also efficacious. We report two cases of atezolizumab-induced hypophysitis. Both showed isolated ACTH deficiency, suggesting similar clinical characteristics of hypophysitis associated with the use of anti-PD-1 antibodies. These results suggest a caution for the late-onset central adrenal insufficiency associated with hypophysitis in patients treated with anti-PD-L1 antibodies.