Anna Maria Formenti

THYREOTROPIN LEVELS IN DIABETIC PATIENTS ON METFORMIN TREATMENT

OBJECTIVE A retrospective study to evaluate the changes in TSH concentrations in diabetic patients treated or not treated with metformin and/or L-thyroxine (L-T(4)). METHODS Three hundred and ninety three euthyroid diabetic patients were divided into three groups on the basis of metformin and/or L-T(4) treatment: Group (M-/L-), 119 subjects never treated with metformin and L-T(4); Group (M+/L-), 203 subjects who started metformin treatment at recruitment; and Group (M+/L+), 71 patients on L-T(4) who started metformin recruitment. RESULTS The effect of metformin on serum TSH concentrations was analyzed in relation to the basal value of TSH (below 2.5 mIU/L (Q1) or between 2.51 and 4.5 mIU/L (Q2)). In patients of group M+/L+, TSH significantly decreased independently from the basal level (Q1, from 1.450.53 to 1.011.12 mU/L (P=0.037); Q2, from 3.600.53 to 1.910.89 mU/L (P<0.0001)). In M+/L group, the decrease in TSH was significant only in those patients with a basal high-normal serum TSH (Q2: from 3.24±0.51 to 2.27±1.28 mU/l (P=0.004)); in M-/L- patients, no significant changes in TSH levels were observed. In patients of group M+/L showing high-normal basal TSH levels, a significant decrease in TSH was observed independently from the presence or absence of thyroid peroxidase antibodies (ABTPO; Q2 ABTPO +: from 3.38±0.48 to 1.87±1.08 mU/l (P<0.001); Q2 AbTPO -: from 3.21±0.52 to 2.34±1.31 mU/l (P<0.001)). CONCLUSIONS These data strengthen the known TSH-lowering effect of metformin in diabetic patients on L-T(4) treatment and shows a significant reduction of TSH also in euthyroid patients with higher baseline TSH levels independently from the presence of AbTPO.

Oral Liquid l-Thyroxine (l-T4) May Be Better Absorbed Compared to l-T4 Tablets Following Bariatric Surgery

Drug malabsorption is a potential concern after bariatric surgery. We present four case reports of hypothyroid patients who were well replaced with thyroxine tablets to euthyroid thyrotropin (TSH) levels prior to Roux-en-Y gastric bypass surgery. These patients developed elevated TSH levels after the surgery, the TSH responded reversibly to switching from treatment with oral tablets to a liquid formulation.

Structural and functional imaging study in dementia with Lewy bodies and Parkinson's disease dementia

INTRODUCTION Dementia with Lewy Bodies (DLB) and Parkinsons disease with Dementia (PDD) are neurodegenerative disorders with complex clinical picture (parkinsonism, cognitive decline and neuropsychiatric disturbances). The conundrum of whether DLB and PDD represent the same or different entities is still under debate. Advanced neuroimaging techniques may represent a point of view to assess brain correlates in DLB and PDD. The study aimed at evaluating whether DLB and PDD may be labelled under the same disease entity or be considered distinctive pathologies. We compared DLB and PDD patients by assessing structural and functional brain imaging and including PD patients. METHODS Patients with diagnosis of PD, PDD, DLB and a group of healthy controls for neuroimaging comparisons were recruited and changes in structural and resting-state functional MR (Regional Homogeneity, ReHo) were studied. RESULTS No significant atrophy in VBM analysis was evident in PD. Conversely, PDD showed a significant bilateral frontal atrophy, whereas DLB was characterized by a predominant parietal, occipital atrophy; a similar involvement of subcortical regions in PDD and DLB was observed. ReHo demonstrated reduced local coherence of frontal regions in PD and in PDD, whereas DLB patients presented a reduced local connectivity in posterior regions. CONCLUSION Different brain areas are specifically involved in PDD and DLB. In the former group, greater atrophy of frontal regions with concomitant functional connectivity impairment was evident; conversely, structural and functional damage in the posterior regions characterized DLB. Despite an overlapping clinical spectrum, DLB and PDD have different networks involved and different underlying pathogenic pathways.

Effect of TMEM106B Polymorphism on Functional Network Connectivity in Asymptomatic GRN Mutation Carriers

IMPORTANCE Granulin (GRN) mutations represent one of the most frequent genetic causes of inherited frontotemporal dementia. The study of asymptomatic carriers of GRN Thr272fs mutation (aGRN+) provides a unique opportunity to study the natural history of the disease and the role of modulating factors on disease onset. It has been demonstrated that the TMEM106B polymorphism is associated with GRN-related frontotemporal dementia and affects age at onset in GRN mutation carriers. OBJECTIVE To ascertain whether TMEM106B genetic status modulates GRN disease by evaluating resting-state functional connectivity in aGRN+ individuals according to TMEM106 genetic variation. DESIGN, SETTING, AND PARTICIPANTS Academic tertiary referral center for neurodegenerative disorders in 17 asymptomatic carriers of aGRN+ and 14 healthy controls. MAIN OUTCOMES AND MEASURES Changes in resting-state functional connectivity, focusing on the default mode network, ventral and dorsal salience networks, executive network, frontoparietal networks, and attentive network and the effect of TMEM106B genotypes in aGRN+ participants and healthy controls (statistical nonparametric mapping). RESULTS aGRN+ participants showed decreased brain connectivity within the left frontoparietal network and increased connectivity in the executive network compared with healthy controls. The TMEM106B at-risk polymorphism (T/T) was associated with decreased connectivity within the ventral salience network (ie, middle frontal gyrus) and the left frontoparietal network (ie, left precuneus). CONCLUSIONS AND RELEVANCE This study suggests that the TMEM106B polymorphism modulates brain connectivity in aGRN+ individuals, with additional damage of the ventral salience network and left frontoparietal network observed. Genotyping TMEM106B is of importance in aGRN+ individuals for prognostic purposes and to assess early brain damage.

Glucocorticoid-induced osteoporosis: pathophysiological role of GH/IGF-I and PTH/VITAMIN D axes, treatment options and guidelines

Glucocorticoid-induced osteoporosis is the most frequent form of secondary osteoporosis caused by chronic exposure to glucocorticoid excess. Pathogenesis of glucocorticoid-induced osteoporosis is multifactorial including direct effects of glucocorticoids on bone cells and indirect effects of glucocorticoids on several neuroendocrine and metabolic pathways. Fragility fractures occur early in glucocorticoid-induced osteoporosis and anti-osteoporotic drugs along with calcium and vitamin D should be started soon after exposure to glucocorticoid excess. This paper summarizes some of the main topics discussed during the 9th Glucocorticoid-Induced Osteoporosis Meeting (Rome, April 2016) with a specific focus on the role of growth hormone/insulin-like growth factor-1 and parathyroid hormone/vitamin D axes in the pathogenesis of glucocorticoid-induced osteoporosis and the controversial aspects concerning therapeutic approach to skeletal fragility in this clinical setting.

TREATMENT OF HYPOTHYROIDISM:ALL THAT GLITTERS IS GOLD?

Levothyroxine (L-T4) is recommended worldwide for replacement therapy of hypothyroidism due to its efficacy in resolving the symptoms, long-term experience of its benefits, long serum half-life, and low cost. Since the isolation of L-T4 by Kendall in 1914 [1] and then the synthesis of T4 and its better absorbed sodium salt [2], it has become the therapy of choice, also due to the demonstration that about 80 % of biologically active tri-iodiothyronine is derived from peripheral conversion of T4 [3]. The individually tailored dose of L-T4 therapy depends on different factors such as body weight, lean body mass, pregnancy status, degree of thyrotropin (TSH) elevation, age, comorbidities, etiology of hypothyroidism, and consequently amount of residual functional thyroid tissue. Therefore, thyroid hormone need may considerably vary among patients. As a matter of fact, although therapy is given correctly, overas well as under-treatment may quite frequently be observed in clinical practice with relevant impact on different clinical outcomes. Indeed, complications of under-treatment are detrimental effects on the serum lipid profile [4], progression of atherosclerotic cardiovascular disease [5], and congestive heart failure [6]. Nowadays, evidence-based guidelines recommend 1 h interval between L-T4 tablet ingestion and breakfast to achieve the best therapeutic effects [7]. The absorption of an orally daily administered dose of L-T4 is about 70–80 % under optimal fasting conditions [8]. Nevertheless, almost 50 % of treated patients show persistently abnormal thyroid functional tests 1 year after starting treatment [9]. This may be due, at least in part, as for many other chronic treatments [10], to compliance problems. Specifically, a subset of patients find difficult or even unfeasible, due for example to work requirements, to comply with the indication of assuming the tablet 1 h before breakfast. This often leads to disproportioned increase in doses of L-T4 and improper or expensive work-up [11]. Moreover, different pathologic conditions, such as atrophic and Helicobacter Pylori-related gastritis or celiac disease, could reduce the rate of absorption of L-T4 via modification of the gastric acid pH, that is essential for complete dissolution of the tablet [12, 13]. Furthermore, soy products and several drugs, such as calcium carbonate, bile acid sequestrants, proton pump inhibitors, and ferrous sulfate, may alter L-T4 absorption [7]. Trying to improve these pharmacokinetic drawbacks, recently new formulations of L-T4 have been introduced: soft gel capsules, containing T4 dissolved in glycerin, and the liquid formulation (only in a few countries). These preparations have been reported to reach the systemic circulation more quickly since gastric dissolution is not needed [14]. In a recent two-year prospective study involving hypothyroid patients without malabsorption or drug interference, Fallahi et al. reported higher effectiveness of liquid L-T4 formulation in normalizing TSH levels as compared to L-T4 tablets [15]. Indeed, the alcoholic component of the liquid formulation could play a crucial role favouring the direct absorption by the highly vascularized oral mucosa [16] and the L-T4 new formulations seem to offer the chance to overcome malabsorption determined by breakfast interference. In fact, it is known & Andrea Giustina a.giustina@libero.it

Vascular Risk Factors and Cognition in Parkinson’s Disease

Vascular risk factors have been associated with cognitive deficits and incident dementia in the general population, but their role on cognitive dysfunction in Parkinsons disease (PD) is still unclear. The present study addresses the single and cumulative effect of vascular risk factors on cognition in PD patients, taking clinical confounders into account. Standardized neuropsychological assessment was performed in 238 consecutive PD patients. We evaluated the association of single and cumulative vascular risk factors (smoking, diabetes, hypercholesterolemia, hypertension, and heart disease), with the diagnosis of PD normal cognition (PDNC, n = 94), mild cognitive impairment (PD-MCI, n = 111), and dementia (PDD, n = 33). The association between single neuropsychological tests and vascular risk factors was evaluated with covariance analyses adjusted for age at onset, educational levels, gender, disease duration, and motor performance. Age, educational levels, disease duration, and motor function were significantly different between PDNC, PD-MCI, and PDD. Heart disease was the only vascular factor significantly more prevalent in PDD compared with PDNC in adjusted analyses. Performance of tests assessing executive and attention functions were significantly worse in patients with hypertension, heart disease, and/or diabetes (p <  0.05). Heart disease is associated with dementia in PD, suggesting a potential window of intervention. Vascular risk factors act especially on attention and executive functions in PD. Vascular risk stratification may be useful in order to identify PD patients with a greater risk of developing dementia. These findings need to be verified in longitudinal studies.

MANAGEMENT OF ENDOCRINE DISEASE: Risk of overtreatment in patients with adrenal insufficiency: current and emerging aspects

The effects of long-term replacement therapy of adrenal insufficiency (AI) are still a matter of controversy. In fact, the established glucocorticoid replacement regimens do not completely reproduce the endogenous hormonal production and the monitoring of AI treatment may be a challenge for the lack of reliable clinical and biochemical markers. Consequently, several AI patients are frequently exposed to relative glucocorticoid excess potentially leading to develop chronic complications, such as diabetes mellitus, dyslipidemia, hypertension and fragility fractures with consequent impaired QoL and increased mortality risk. This review deals with the pathophysiological and clinical aspects concerning the over-replacement therapy of primary and secondary AI.

Subcortical and Deep Cortical Atrophy in Frontotemporal Dementia due to Granulin Mutations

Background/Aims: Parkinsonism is often associated with symptoms of frontotemporal dementia (FTD), but its pathogenesis has been largely neglected. In genetic inherited FTD-related granulin (GRN) mutations, parkinsonism is an early sign, and it is more common than in sporadic disorders. Our aim was to study grey matter (GM) volume changes in subcortical and deep cortical regions in GRN-related FTD. Methods: A total of 33 FTD patients (13 carriers of the GRN mutation, GRN+, and 20 non-carriers, GRN-) and 12 healthy controls (HC) were included in the study. Each subject underwent an MRI examination (1) for voxel-based morphometry to study GM differences in cortical and subcortical regions, and (2) for a region of interest approach using a probabilistic atlas of subcortical regions (caudate nucleus, putamen, thalamus and amygdala) to assess the regional differences. Results: The GRN+ group showed greater damage in frontotemporal regions than the GRN- group. The FTD patients had greater GM atrophy in the caudate nucleus and in the thalamus bilaterally than the HC. Damage to these subcortical and deep cortical regions was greater in the GRN+ than in the GRN- patients. Discussion: Subcortical and deep cortical involvement is a key feature of FTD, and more pronounced in GRN-related disease. Damage to the caudate region in GRN+ patients may explain the parkinsonism frequently associated since the early stages of the disease.

High-Dose and High-Frequency Lanreotide Autogel in Acromegaly: A Randomized, Multicenter Study.

Context Increase in drug frequency or dose is recommended for acromegaly patients with partial response to long-acting somatostatin receptor ligands (SRLs). However, the efficacy and safety data with lanreotide (LAN) Autogel (LAN-ATG) at high dose (HD) or high frequency (HF) are still scanty. Objective To evaluate the biochemical efficacy and safety of HF and HD LAN-ATG in patients with active acromegaly. Design Twenty-four-week prospective, multicenter, randomized, open-label trial. Patients and Interventions Thirty patients with active acromegaly, partial responders to SRLs, were randomized to HF (120 mg/21 days; 15 patients) or HD (180 mg/28 days; 15 patients) LAN-ATG. Outcomes Normalization of serum insulin-like growth factor-I (IGF-I) and reduction in random growth hormone (GH) values < 1.0 µg/L, reduction in serum IGF-I and GH from baseline, differences in biochemical response between HF and HD LAN-ATG, adverse events. Results IGF-I decreased significantly (P = 0.007) during the 24-week treatment, with greater decrease in HD (P = 0.03) vs HF group (P = 0.08). Normalization in IGF-I values occurred in 27.6% of patients (P = 0.016 vs baseline), without a significant difference between HF and HD groups (P = 0.59). The decrease in serum IGF-I significantly correlated with serum LAN values (P = 0.04), and normalization of IGF-I was predicted by baseline IGF-I values (P = 0.02). Serum GH values did not change significantly (P = 0.22). Overall, 19 patients (63.3%) experienced adverse events, all being mild to moderate and transient, without differences between the two therapeutic arms. Conclusion HF and HD LAN-ATG regimens are effective in normalizing IGF-I values in about one-third of patients with active acromegaly inadequately controlled by long-term conventional SRLs therapy.