Clinical features and therapeutic outcomes of acromegaly during the recent 10 years in a single institution in Japan.

Untreated acromegaly is associated with a twofold to fourfold increased mortality risk compared to the population. Recently, new therapeutic modalities have been developed and may contribute to an improvement in treatment outcomes in patients with acromegaly. In the current study we determined the clinical features and recent therapeutic outcomes in patients with acromegaly. The initial symptoms, selected therapeutic modalities, and outcomes in 125 patients with acromegaly (M/F, 49/76, 19-86 years) who were admitted to our institution between 2001 and 2010 were analyzed using medical charts. The basal GH levels and IGF-I SD scores in the patients ranged from 0.17 to 90.21 µg/L and 1.9-13.6, respectively. Acral enlargement (face, hands, and feet) without overt complications was essential to the diagnosis in 49 % of the patients. In these cases, it required 5 years to establish the diagnosis of acromegaly after symptom onset. Twenty (16 %) and 13 (10 %) patients had diabetes mellitus and hypertension 6 years prior to the diagnosis of acromegaly, respectively. In 35 patients with microadenomas, the rate of controlled cases following transsphenoidal surgery was 93 %. In 90 patients with macroadenomas, the remission rate was 79 % with multidisciplinary treatment. In cases in which the tumor extended beyond the lateral tangent of the internal carotid artery (Knosp grade ≥3), the remission rate was 33-56 %. Improvements in surgical techniques and medical therapies may contribute to increased rates of controlled cases in patients with acromegaly, although advanced lateral extension of the tumor remains a critical determinant of the therapeutic outcome.

Effects of GH assay standardization on evaluation of treatment outcomes for acromegaly in Japan.

In Japan, the growth hormone (GH) assay has been standardized since April 2005 through use of a uniform recombinant human GH (rhGH) standard. Since then, GH values measured using the rhGH standard have been approximately 40% lower than previous values measured using kit standards based on the WHO standards for hGH of pituitary origin. However, the Japanese criteria for evaluating treatment outcomes for acromegaly have remained the same: a nadir GH during a 75 g OGTT <1 µg/L is considered cured, 1≤GH<2.5µg/L is considered inadequately controlled, and ≥2.5 µg/L is considered poorly controlled, instead of these levels were lowered to 60%, i.e. from 1 to 0.6 µg/L for cured and from 2.5 to 1.5µg/L for inadequately controlled (termed as "newly proposed criteria" in this study). We investigated the effects of standardization of the GH assay on the evaluation of post-surgical disease activity in 50 patients with acromegaly (M/F 19/31, 21-72 yr.). Post-surgical nadir GH levels during OGTT were positively correlated with the IGF-I SD score 3 months after TSS. Five of 6 patients whose post-surgical nadir GH levels ranged between 0.6 and 1 µg/L had normal serum IGF-I levels 3 months after TSS. Rates of improvement in glucose metabolism did not differ when patients were classified based on the present criteria vs. the newly proposed criteria. In conclusion, the current Japanese remission criteria for acromegaly still accurately reflect post-surgical disease activity in most patients, though long-term observation is still required.

Autoimmune thyroid diseases in 65 Japanese women with Turner syndrome.

Turner syndrome (TS) is associated with a number of complications including thyroid disease. In this study, the prevalence of thyroid disease was evaluated in Japanese women with TS. The medical charts of 65 TS women (age 30+/-9 years old, range: 15-61), treated with estrogen replacement therapy or with antiosteoporotic pharmaceuticals at our outpatient clinic, were reviewed. History of thyroid disease, titer of thyroid autoantibodies, and thyroid function were recorded. Thyroid autoantibodies were undetectable in 28 of 65 women (43%), and thyroid function was normal in all these women. Of the 37 women with thyroid autoantibodies (57%), 3 had Graves' disease and 20 women were hypothyroidism and diagnosed as Hashimoto' s thyroiditis. The resting 14 women with euthyroidism were also considered to be so-called probable cases of Hashimoto' s thyroiditis. In 20 women with hypothyroidism, 14 (70%) received replacement therapy with levothyroxine. The replacement with levothyroxine started between age 17 and 60 (median: 31 years old). These data showed that more than half of Japanese women with TS in adulthood had thyroid autoantibodies. In women with TS, monitoring of thyroid hormone is important to detect hypothyroidism earlier and start adequate replacement therapy.

Increased thyroid blood flow in the hypoechoic lesions in patients with recurrent, painful Hashimoto's thyroiditis at the time of acute exacerbation.

We report two cases with painful Hashimoto's thyroiditis, who developed recurrent fever and painful thyroid. Glucocorticoid treatment was transiently successful but tenderness in the thyroid gland and fever developed when glucocorticoid was tapered. One patient underwent total thyroidectomy uneventfully. As is well known, it is frequently difficult to make differential diagnosis between painful Hashimoto's thyroiditis and subacute thyroiditis particularly at the initial phase. Interestingly, color flow doppler sonography of patient 1 revealed an increased thyroid blood flow in the hypoechoic lesions at the time of acute exacerbation although the serum level of TSH was suppressed. In the other patient, thyroid blood flow was also increased mainly in the hypoechoic lesions when the serum level of TSH was moderately increased, and it disappeared completely after supplementation of prednisolone and L-T4. Since thyroid blood flow in subacute thyroiditis is always decreased, such an increased blood flow in the hypoechoic lesion may be one of clinical characteristics of painful Hashimoto's thyroiditis, and useful for differential diagnosis from subacute thyroiditis.

Metabolic co-morbidities revealed in patients with childhood-onset adult GH deficiency after cessation of GH replacement therapy for short stature.

GH therapy was approved in 2006 for treatment of adult growth hormone deficiency (GHD) in Japan. Until then, GH was used only to treat short stature in children with GHD and the treatment was stopped when the final height was reached. In the present study, we investigated metabolic co-morbidities experienced by adults with childhood-onset (CO) GHD after the cessation of GH. Forty-two patients with COGHD (M/F 22/20, age at follow up when the retrospective analysis was carried out: 18-52 yr) treated with GH in childhood were studied. We reviewed the medical records of these patients to determine the metabolic co-morbidities that developed after cessation of GH. The median age was 19 yrs (range: 14-38) at cessation of GH, and the following co-morbidities were observed: hypertriglyceridemia in 15 (41%) patients, non-alcoholic fatty liver disease (NAFLD) in 11 (29%) patients, hypercholesterolemia in 10 (26%) patients, diabetes mellitus (DM) in 4 (10%) patients, and hypertension in 1 (2.4%) patient. The median BMI when these complications became overt was 23.5 kg/m(2) for those with hypertriglyceridemia, 26.0 kg/m(2) for those with NAFLD, 20.9 kg/m(2) for those with hypercholesterolemia, and 27.2 kg/m(2 ) for those with DM. More than two co-morbidities were experienced by 32% of men and 30% of women. In conclusion, adults with COGHD after the cessation of GH have multiple metabolic co-morbidities. Lifelong GH replacement might be important for improving the overall metabolic profiles in these patients.

The prevalence of benign and malignant tumors in patients with acromegaly at a single institute.

It has been reported that patients with acromegaly may have an increased risk of developing several types of cancers, such as colorectal, breast and prostate tumors. However, some reports do not support these findings and therefore the prevalence of cancers in patients with acromegaly remains controversial. In this study, we determined the prevalence of benign and malignant neoplasms in patients with acromegaly. A retrospective chart analysis was performed on 140 patients with active acromegaly who had attended our outpatient clinic (M/F 54/86, age 55 +/- 25 yr, range 21-86). Colon cancer was found in 10 patients, thyroid cancer in 5, breast cancer in 4 and gastric cancer in 2. When compared with the local population, the standardized incidence ratios (SIRs) for thyroid cancer in patients with acromegaly were 61.74 (95% confidence interval (CI): 0.51-114.63) for females and 272.4 (95% CI: 29.12-876.71) for males. The SIRs for colon cancer in the acromegalic patients were 17.4 (95% CI: 4.74-44.55) for females and 19.0 (95% CI: 5.18-48.64) for male patients in comparison with the local population. Of the benign tumors, multinodular goiter and colonic, gastric and gallbladder polyps were observed in 57% (47/83), 40% (35/87), 23% (10/43), and 14% (11/77) [corrected] of the patients, respectively. This study suggested that patients with acromegaly have an increased risk of colon cancer and polyps. Moreover, it is speculated that the risk for thyroid cancer is increased in male patients. It is therefore recommended that patients with acromegaly should undergo screening colonoscopy and ultrasonography of the thyroid.

Clinical features of insulin-like growth factor-II producing non-islet-cell tumor hypoglycemia.

In some patients with non-islet-cell tumor hypoglycemia (NICTH), a high molecular weight form of IGF-II (big IGF-II) derived from tumors is present in the circulation and might be associated with recurrent hypoglycemia. In this study, in order to survey the clinical characteristics of patients with IGF-II producing NICTH, we analyzed the medical records of 78 patients with NICTH (M/F 44/34, age 62+/-1.8, range; 9-86 years.) whose serum contained a large amount of big IGF-II. Hepatocellular carcinoma and gastric carcinoma were the most common causes of NICTH. The diameters of the tumors were more than 10 cm in 70% of the patients. Basal immunoreactive insulin (IRI) levels were less than 3 microU/dl in 79% of the patients. Hypoglycemic attack was the onset of disease in 31 of 65 cases (48%), but the tumor was revealed prior to the occurrence of hypoglycemia in 34 cases (52%). Twenty-five of 47 (53%) patients had decreased serum potassium levels. These data suggested that hypoinsulinemic hypoglycemia associated with the presence of a large tumor supports the diagnosis of IGF-II producing NICTH. Hypokalemia was associated with hypoglycemia in some patients. The BMI (21.4+/-0.6 kg/m2) and serum total protein levels (6.6+/-0.1g/dl) were preserved at the occurrence of first hypoglycemic attack suggesting that malnutrition might not be the main cause of hypoglycemia in most patients.

Serum adiponectin levels in adult growth hormone deficiency and acromegaly.

Atherosclerosis and insulin resistance are common complications of adult growth hormone deficiency (GHD) and acromegaly. Circulating adiponectin, an adipocyte-derived protein, has both anti-atherogenic and insulin-sensitising effects. In this study, we measured serum adiponectin levels in patients with either adult GHD or acromegaly to clarify the impact of GH secretory states on the regulation of serum adiponectin levels. Serum adiponectin level was measured by radioimmunoassay in 32 patients with adult GHD, 49 patients with acromegaly and 25 normal subjects. The relationships between adiponectin and insulin sensitivity index assessed as quantitative insulin sensitivity check index (QUICKI), BMI, and serum GH and IGF-I levels were then investigated. The values of QUICKI were significantly lower in patients with acromegaly or adult GHD compared to normal subjects (0.33 +/- 0.03, P < 0.01, 0.35 +/- 0.04, P < 0.05 and 0.36 +/- 0.01, respectively). While patients with adult GHD had significantly lower serum adiponectin levels than patients with acromegaly (6.5 +/- 3.9, 9.2 +/- 5.0, P < 0.01) these levels were not significantly different from those found in normal subjects (7.8 +/- 4.3 mug/ml). There was an inverse correlation between serum adiponectin levels and BMI in both patient groups (GHD r = -0.39, P < 0.05; Acromegaly r = -0.35, P < 0.05). However, serum adiponectin levels correlated positively with QUICKI (R(s) = 0.37, P < 0.05) only in patients with adult GHD. In patients with acromegaly, the levels of circulating adiponectin showed an inverse correlation with serum IGF-I levels (R(s) = -0.34, P < 0.05), but not with basal GH levels. These results demonstrate that adiponectin levels are significantly lower in patients with adult GHD than in patients with acromegaly. Adiponectin levels are similar in patients with GHD and healthy controls, whereas in patients with acromegaly, insulin resistance appears to be not closely related to adiponectin levels compared with BMI. The different relationship between adiponectin and QUICKI observed in the adult GHD and acromegaly groups presumably reflects differences in the mechanisms of insulin resistance under states of GH deficiency or excess.