Florina Luca

Pituitary MRI characteristics in 297 acromegaly patients based on T2-weighted sequences

Responses of GH-secreting adenomas to multimodal management of acromegaly vary widely between patients. Understanding the behavioral patterns of GH-secreting adenomas by identifying factors predictive of their evolution is a research priority. The aim of this study was to clarify the relationship between the T2-weighted adenoma signal on diagnostic magnetic resonance imaging (MRI) in acromegaly and clinical and biological features at diagnosis. An international, multicenter, retrospective analysis was performed using a large population of 297 acromegalic patients recently diagnosed with available diagnostic MRI evaluations. The study was conducted at ten endocrine tertiary referral centers. Clinical and biochemical characteristics, and MRI signal findings were evaluated. T2-hypointense adenomas represented 52.9% of the series, were smaller than their T2-hyperintense and isointense counterparts (P<0.0001), were associated with higher IGF1 levels (P=0.0001), invaded the cavernous sinus less frequently (P=0.0002), and rarely caused optic chiasm compression (P<0.0001). Acromegalic men tended to be younger at diagnosis than women (P=0.067) and presented higher IGF1 values (P=0.01). Although in total, adenomas had a predominantly inferior extension in 45.8% of cases, in men this was more frequent (P<0.0001), whereas in women optic chiasm compression of macroadenomas occurred more often (P=0.0067). Most adenomas (45.1%) measured between 11 and 20 mm in maximal diameter and bigger adenomas were diagnosed at younger ages (P=0.0001). The T2-weighted signal differentiates GH-secreting adenomas into subgroups with particular behaviors. This raises the question of whether the T2-weighted signal could represent a factor in the classification of acromegalic patients in future studies.

T2-weighted MRI signal predicts hormone and tumor responses to somatostatin analogs in acromegaly.

GH-secreting pituitary adenomas can be hypo-, iso- or hyper-intense on T2-weighted MRI sequences. We conducted the current multicenter study in a large population of patients with acromegaly to analyze the relationship between T2-weighted signal intensity on diagnostic MRI and hormonal and tumoral responses to somatostatin analogs (SSA) as primary monotherapy. Acromegaly patients receiving primary SSA for at least 3 months were included in the study. Hormonal, clinical and general MRI assessments were performed and assessed centrally. We included 120 patients with acromegaly. At diagnosis, 84, 17 and 19 tumors were T2-hypo-, iso- and hyper-intense, respectively. SSA treatment duration, cumulative and mean monthly doses were similar in the three groups. Patients with T2-hypo-intense adenomas had median SSA-induced decreases in GH and IGF-1 of 88% and 59% respectively, which were significantly greater than the decreases observed in the T2-iso- and hyper-intense groups (P < 0.001). Tumor shrinkage on SSA was also significantly greater in the T2-hypo-intense group (38%) compared with the T2-iso- and hyper-intense groups (8% and 3%, respectively; P < 0.0001). The response to SSA correlated with the calculated T2 intensity: the lower the T2-weighted intensity, the greater the decrease in random GH (P < 0.0001, r = 0.22), IGF-1 (P < 0.0001, r = 0.14) and adenoma volume (P < 0.0001, r = 0.33). The T2-weighted signal intensity of GH-secreting adenomas at diagnosis correlates with hormone reduction and tumor shrinkage in response to primary SSA treatment in acromegaly. This study supports its use as a generally available predictive tool at diagnosis that could help to guide subsequent treatment choices in acromegaly.

In vivo evidence for a direct ultra‐fast negative feedback of thyroxine on TSH secretion in humans: a case of L‐thyroxine pseudomalabsorption

Pseudomalabsorption of levothyroxine is a factitious disorder suggesting malabsorption of levothyroxine. One of the therapeutic possibilities for treating hypothyroidism is the once weekly supervised administration of a large dose of thyroxine. 1 We describe such a patient with whom we had the opportunity to follow hormonal concentrations after each dose of thyroxine. A 55-year-old man ( weight 60 kg ) was referred because of persistent hypothyroidism (TSH 200 mU/l, N = 0·15–4·5) despite relatively high doses of levothyroxine (200 μ g/day). He had undergone thyroidectomy for ‘uncontrolled hyperthyroidism’ in another hospital two years before. The retrospective review of his chart led us to suspect noncompliance with his thyroxine replacement therapy. Clinical examination was unremarkable; pulse was regular at 60 beats/min; the patient had no complaint and reported taking his levothyroxine regularly every morning. Pseudomalabsorption was diagnosed and advice given to the patient. He was admitted 6 months later at the emergency unit with a spontaneous cutaneous haematoma. This episode was probably related to the surreptitious taking of warfarin but again the patient denied taking any drug other than levothyroxine. At the time of the hospitalization, TSH was about 200 mU/l. There were no clinical or biological signs of malabsorption and upper endoscopy with duodenal biopsies was normal. To verify thyroxine absorption, we administered a large dose of thyroxine under medical supervision and then took blood samples to assess TSH and thyroid hormone concentrations. As the first procedure confirmed the efficacy of this modality of treatment and excellent tolerance, he was then asked to return once a week to continue his treatment. Once per week, at 08·00 h as he was fasting, he was orally administered 1000 μ g of levothyroxine under the supervision of a nurse. During the first 10 weeks of thyroxine charge, TSH decreased by 39 ± 6% of the initial values 2 h after oral thyroxine administration, with great consistency each week, whatever the initial TSH levels (ranging from 178 to 2·53 mU/l). The decrease continued more slowly during the subsequent 6 h to about 60% of the initial values after 8 h. At the same time, free T4 (FT4) increased by twoto threefold the initial values, peaked between the second to third hour and then declined very slowly. As expected, there was no significant variation in free T3 (FT3) levels after 2 h and then a very slight increase 4 h and 6 h after the charge. After analysing the first results, the patient agreed to one session with blood sampling every 15 min for the first 2 h to allow us more detailed kinetics studies (Fig. 1). TSH decreased from 108 mU/l to 95·8 mU/l after 15 min and to 87·5 mU/l after 30 min. At the same time, FT4 increased from 8·44 pmol/l to 11·67 pmol/l and then to 19·6 pmol/l, whereas FT3 increased slightly from 3·67 pmol/l to 3·78 pmol/l and then to 3·93 pmol/l. The peak of FT4 levels was observed 1 h after thyroxine ingestion, whereas that of FT3 appeared biphasic with the first maximum 1 h after ingestion and a second peak 2 h after ingestion. Alpha subunit was at relatively high levels before treatment and exhibited large fluctuations after thyroxine administration without a clear pattern. Several months after the beginning of the weekly thyroxine treatment, TSH on the day of dosing varies between 2 mU/l and 10 mU/l and the patient remains asymptomatic. The inhibitory effect of thyroxine on TSH secretion is classically due to the pituitary conversion of T4 to T3 by type 2 deiodinase (DT2), with subsequent repression of TSH synthesis by the genomic effects of T3. In thyroidectomized rats, the administration of T4 or of T3 is rapidly associated with an increase in T3 nuclear receptor occupancy and a decrease in TSH levels. 2 In this model, TSH suppression is dependent upon nuclear T3 content and serum T3 concentration. 3 When iopanoic acid (an inhibitor of T4 to T3 conversion) is given to rats, it prevents the decrease of TSH provoked by the administration of T4. However, in none of these papers, was plasma TSH measured as early after T4 administration as in our study. Several authors have studied the kinetics of the negative feedback of thyroid hormone on TSH in man but most have used T3, either orally or intravenously, and the beginning of the decrease of TSH was not always precisely mentioned. Spencer et al . have studied in detail the kinetics of plasma TSH after a single oral or intravenous dose of T3 both in euthyroid and in hypothyroid subjects. 4 They defined a two-phase response beginning 1–4 h after thyroid hormone administration with a fall of 25–50% in TSH levels, a decrease of the same amplitude as that observed in our patient. This effect likely relies on the release of preformed TSH stores, because the effect on TSH synthesis requires several hours. This hypothesis is also sustained in our patient by the absence of inhibition of subunit α release, which is known to be controlled in a different way than that of mature TSH. In other studies using oral thyroxine administration, the peak of serum T4 was observed 2–3 h after the administration, and TSH responses during the first 10 h were not generally mentioned. Recent papers have shown the complexity of the regulation of DT2. 5 Briefly, DT2 is up-regulated in hypothyroidism but is also stimulated by T4. This could partly explain the rapidity of the TSH decrease at the beginning of treatment of hypothyroidism, a situation

Mise au pointHyperglycémie dans les maladies aiguës : signification et prise en chargeHyperglycemia in the critically ill: meaning and treatment

Hyperglycemia is commun in critically ill patients without previously known diabetes. Hyperglycemia occurring in these patients is mainly a consequence of stress associated to complex glucose metabolism abnormalities which have deleterious effects on tissues and vascular function. Several epidemiologic and intervention studies had established that hyperglycemia is related to morbidity and mortality. Maintenance of normoglycemia with intensive insulin therapy seems to decrease morbidity and mortalities in severe acute illnesses. However the benefit of most of these intervention trials remain controversial mainly in stroke, myocardial infarction and severe sepsis. Moreover strict normoglycemia required to obtain an optimal benefit increases the risk of hypoglycaemia which may be particularly harmful in patients in critical state.

Hyperglycémie dans les maladies aiguës : signification et prise en charge

Hyperglycemia is commun in critically ill patients without previously known diabetes. Hyperglycemia occurring in these patients is mainly a consequence of stress associated to complex glucose metabolism abnormalities which have deleterious effects on tissues and vascular function. Several epidemiologic and intervention studies had established that hyperglycemia is related to morbidity and mortality. Maintenance of normoglycemia with intensive insulin therapy seems to decrease morbidity and mortalities in severe acute illnesses. However the benefit of most of these intervention trials remain controversial mainly in stroke, myocardial infarction and severe sepsis. Moreover strict normoglycemia required to obtain an optimal benefit increases the risk of hypoglycaemia which may be particularly harmful in patients in critical state.