Angelo Acquafredda

Risk Factors for Subclinical Atherosclerosis in Diabetic and Obese Children

Background. Increased carotid intima-media thickness (cIMT) is considered a marker of early-onset atherosclerosis and it seems to predict cardiovascular events both in obese and diabetic subjects. We aimed to evaluate early signs of atherosclerosis and investigate for predisposing factors in children and adolescents affected by type 1 diabetes (T1DM) or obesity, comparing them with healthy controls. Methods. Out of 71 enrolled subjects (mean age 12.8 ± 2.3 years), 26 had T1DM and 24 were obese, while 21 age- and sex-matched subjects acted as controls. cIMT was measured using standardized methods. Serum glucose, insulin, cholesterol, triglycerides and C-reactive protein levels were evaluated. An oral glucose tolerance test (OGTT) was performed in obese subjects. Results. Diabetic and obese individuals showed higher cIMT mean values than healthy controls (p<0.005). cIMT of the three examined segments correlated positively with fasting glucose levels and negatively with units of insulin/kg/day administered in T1DM individuals. A positive correlation between insulin levels (basal and after oral glucose load) and cIMT of common, internal and external carotid artery was found in obese subjects (p<0.03). High density cholesterol levels represented a protective factor for cIMT in this latter group of the study population. Conclusions. Our findings show that cIMT correlates with high insulin levels (a sign of insulin resistance) in obese patients and with high fasting glucose levels (a sign of relative insulin deficiency) in T1DM subjects, confirming the need of reducing hyperinsulinism and monitoring blood glucose levels in these subjects to prevent atherosclerosis.

Longitudinal Assessment of Levo-Thyroxine Therapy for Congenital Hypothyroidism: Relationship with Aetiology, Bone Maturation and Biochemical Features

Aims: To evaluate therapy and dose adjustments in patients with congenital hypothyroidism (CH), longitudinally followed up until 16 years old, according to aetiology, Beclard’s nuclei presence, and thyroxine (T4) level at diagnosis. Methods:L-T4/kg/day and dose change ratio (CR) were assessed in 74 CH patients. Results: The dose was statistically larger in athyreosis than in dyshormonogenesis (1–10 and beyond 14 years) and in ectopy (2, 15, 16 years). The ectopic children required statistically larger L-T4/kg than the dyshormonogenetic ones (3–7 years). The L-T4/kg/day was increased, not statistically, in patients or with T4 <30 nmol/l or without Beclard’s nuclei at diagnosis. The CR progressively dropped after the 6th month at each attendance, without any difference in terms of aetiology, T4 level at diagnosis, or Beclard’s nuclei. The total CR was greater (significantly) in patients without Beclard’s nuclei, and (not significantly) in those with T4 <30 nmol/l at diagnosis or with agenesia. Conclusion: The L-T4 dose in CH is highly affected by the aetiology. The CR is higher in patients with delayed bone maturation at diagnosis. We suggest that these latter patients need blood tests more frequently to obtain a proper titration of the therapy.

Factors predicting final height in early treated congenital hypothyroid patients

Objective  To evaluate pubertal development and final height (FH) in early treated patients with congenital hypothyroidism (CH) and to identify the main factors predicting FH.

Propranolol for infantile haemangiomas and neuroglycopenic seizures

Sir, Propranolol has been used since mid 2008 for the treatment of complicated infantile haemangiomas (IHs) at a dose of 2 mg ⁄ kg ⁄ day. A current review of the literature confirmed that this beta-blocker has detached steroids in the therapy for IHs (1). We know of a 6-month-old white boy presenting with generalized seizures. He was born at term, via vaginal delivery, normal for gestational age. Because of multiple cutaneous haemangiomas and multifocal hepatic lesions, at 1 month of age propranolol was started at 2 mg ⁄ kg ⁄ day in three divided doses. Without any preceding illness, seizures occurred at 10:00 AM, after 10 h overnight fasting period, while medication was administered at 6:30 AM. On arrival, his physical examination was unremarkable; vital signs and haemogasanalysis were normal, and serum glucose measurement was 0.83 mmol ⁄ L (15 mg ⁄ dL). Treated with intravenous (IV) bolus of 0.25 g ⁄ kg 10% glucose solution followed by 6 mg ⁄ kg ⁄ min continuous IV infusion of 5% glucose, he progressively regained consciousness. During hospitalization, propranolol was given utilizing gradual dose escalation, according to the treatment protocol of Lawley et al. (2); serum glucose level was checked 2 h after propranolol administration and before meals (values constantly > 4 mmol ⁄ L = 80 mg ⁄ dL) without any further hypoglycaemic episodes. All laboratory investigations were normal, except ketonuria and high serum levels of b-hydroxybutyrate and acetoacetate, representing the starved state. No lesion on cranial MRI; abdominal MRI showed wide reduction of hepatic haemangiomas. His mother stated that during treatment he had progressively become hyperphagic, increasing milk intake (up to 300 mL each meal) as well as the total number of feeds. After delivery, propranolol was continued and no longer he had hypoglycaemic episodes on follow-up. We speculate a multifactorial origin of neuroglycopenic seizures: restricted carbohydrate intake, overnight fast and depleted glycogen stores, in combination with inadequate production of glucose through gluconeogenesis ought to propranolol treatment, could happen in a boy with chronic hypoglycaemia masked by hyperphagia. Checking current literature, we found only three others documented cases of symptomatic hypoglycaemia (3). Many authors documented that on propranolol, normally fed infants are not at risk for hypoglycaemia, but we did not found any mention about details of oral intake. Lawley et al. (2) observed that propranolol may blunt the clinical features of hypoglycaemia reporting occult hypoglycaemia; moreover, they stated that the starting dose of 2 mg ⁄ kg ⁄ day may contribute to adverse events, suggesting a protocol with gradual dose escalation. To prevent hypoglycaemia, we suggest that all infants should have regular food intake and receive medication every day at the same time, preferably every 6 h, before meals (frequent feeds must be encouraged), and never overnight. At home, it is mandatory to instruct parents to control babies for signs and symptoms of hypoglycaemia, while blood pressure and heart rate should be evaluated intermittently. In the ‘propranolol era’, according to our experience, further studies are needed to evaluate the safety of this medication because all hyperphagic infants during treatment may have higher risk of severe hypoglycaemia and should assume tapered dose with close monitoring of glycaemia.

Growth hormone release during insulin tolerance, Clonidine, arginine and growth hormone releasing hormone tests in short normal children and adolescents

This study was retrospectively performed in 574 short normal children and adolescents [328 underwent insulin tolerance test (ITT), 34 Clonidine test (CLON), 64 arginine test (ARG), 19 GHRH test, 52 ITT+CLON, 30 GHRH+CLON, and 47 ITT+CLON+GHRH) in order to evaluate the effect of pubertal stage on G H response to different tests and to identify the most likely mechanism of action of different stimuli. GH peak was higher during GHRH than in all other tests. Sex or start of pubertal development did not cause any GH peak difference. Low-responder (GH peak <10ng/ml) percentages were similar (ITT = 13.5%, CLON = 13.4%, ARG = 13.2%, GHRH = 10.6%) also when the subjects were divided according to sex and pubertal development. ITT+CLON showed discordant results in 42/99 subjects (30/42 = 71.4% were low-responders to ITT and 12/42 = 28.6% to CLON). GH peak appeared earlier during GHRH (85% <45 min) and later during CLON (78%: 60–120 min) than during all other tests; GH peak during ITT showed a wide variability of time. Negative correlations were found between GH peak during GHRH and chronological age, height and bone age and during CLON and chronological age. In conclusion our data show that these tests have similar GH secretagogue reliability.

Final height in short polytransfused thalassemia major patients treated with recombinant growth hormone

We measured the final height (FH) of 25 short polytransfused thalassemia major (Th) patients (18 males) with a reduced GH reserve treated for 3.3±1.2 yr with recombinant GH (rhGH), 0.2 mg/kg/week sc. At baseline, all patients were clinically prepubertal; their chronological (CA) and bone ages (BA) were 13.6±2.0 and 11.4±1.6 yr, respectively. In 9 out of 18 males and 5 out of 7 females, the onset of puberty occurred spontaneously during the treatment. At the end of the rhGH administration, the height of the enrolled children was not significantly increased when calculated for CA (HxCA), while it was significantly decreased (p=0.004) when calculated for BA (HxBA); the BA increase (3.29±1.65 yr) was significantly higher (p<0.001 ) than the height age increase (2.16±0.98 yr). The FHxCA showed a significant increase (p=0.001) compared to both baseline and the end of therapy, while the FHxBA was significantly decreased (p<0.001) compared with the corresponding value at baseline. At the end of therapy, both HxCA and HxBA resulted positively related to the BA at baseline (r=0.50 and 0.42, p=0.012 and 0.034, respectively). FH was positively correlated with CA (r=0.63, p=0.001), BA (r=0.68, p<0.001) and HxBA (r=0.59, p=0.002) evaluated at baseline, and with both HxCA and HxBA (r=0.82 and 0.74, respectively, p<0.001), evaluated at the end of treatment. A negative correlation was found between FH and the length of treatment (r=−0.56, p=0.004). Our data seem to exclude that prolonged rhGH therapy could improve FH in Th patients; on the contrary, a negative effect may be hypothesized.

Recombinant growth hormone treatment in short patients with thalassemia major: results after 24 and 36 months.

Abstract Treatment with recombinant growth hormone (rhGH), 0.6 IU/kg/week s.c., previously successfully conducted for one year, was continued in 15 (Group A) and 8 (Group B) short thalassemia major patients with reduced GH reserve, for two and three years, respectively. In Group A, height for chronological: age (Ht SDSca) increased significantly (p = 0.021) from the start of treatment, but the positive effect was only apparent because of the concomitant slight worsening of height for bone age (Ht SDSba). Median AHt SDScA/AHt SDSba was <1.0 with respect to both the start (0.87) and the end of the first year of rhGH therapy (0.89). IGF-I levels increased significantly (p = 0.043) compared with values both at the start and at the end of the first year of rhGH therapy. In Group B neither Ht SDSca : nor Ht SDSba differed statistically from starting values, the former having a positive trend and the latter a negative one. Median AHt SDScA/AHt SDSba was 0.92 with respect to the start, and 0.94 with respect to the end of the second year. IGF-I levels increased significantly (p = 0.043) with respect to starting values. Our data show that the encouraging results described from the first year of rhGH treatment did not persist during the second and third years, and we conclude that this is because increase in bone age with continued treatment is equal to, or slightly greater than the height age increase. We propose that patients with thalassemia major with short stature should receive rhGH treatment for only one year, and that more prolonged treatment should be reserved for selected adolescents who have psychological problems due to shortness; for these patients growth acceleration could represent the main goal, even if this leads to a substantially unchanged or slightly decreased final height.

Cardiac function in congenital hypothyroidism: Impairment and response to L-T4 therapy

SummaryElectrocardiograms (heart rate, QRS voltage, QRS axis in the frontal plane, Q-Tc interval), echocardiograms [left ventricular fractional shortening (LVFS); preejection period (PEP); PEP/left ventricular ejection time (PEP/LVET) ratio; end-diastolic left ventricular free wall and interventricular septum thickness; presence of pericardial effusion], and thyrotropin (TSH), thyroxine (T4), and triiodothyronine (T3) serum levels were evaluated before and 1 week, 1 and 2 months after the start ofl-thyroxine (L-T4) therapy in 11 infants with congenital hypothyroidism (CH), aged 16–59 days when first seen.Before the start of therapy, infants with CH had significantly lower QRS complexes and LVFS and significantly higher values for Q-Tc, PEP, and PEP/LVET than normal infants of the same age. The QTc interval, PEP and PEP/LVET ratio of infants with CH were significantly greater before than 1 week after L-T4 therapy, and LVFS was significantly lower before than 1 month after L-T4 therapy. Four of the infants with CH had small pericardial effusions, which disappeared within the first week of therapy.QRS axis in the frontal plane, Q-Tc interval, and PEP were negatively correlated with logT4 and logT3 serum levels. PEP/LVET ratios were negatively correlated with logT4 serum values. The QRS voltage values were positively correlated with logT4 and logT3 serum values. The frontal-plane QRS axis, Q-Tc interval, and PEP/LVET ratio were positively correlated with logTSH serum levels. The QRS voltages were negatively correlated with TSH serum levels.Our data show that before therapy infants with CH have the same functional, but not morphological, abnormalities as older hypothyroid ones and that one third of them have small pericardial effusions. L-T4 therapy rapidly reverses these changes.

Diagnostic value of growth hormone-releasing hormone test in children and adolescents with idiopathic growth hormone deficiency

Average growth hormone (GH) peaks following an i.v. growth hormone releasing hormone (GHRH) 1–29 stimulation test were significantly lower in 48 children and adolescents with GH deficiency (GHD) than in 20 age-matched controls (15.2+12.7 vs 37.5+28.1 ng/ml, 2P<0.001). Twelve patients exhibited a low GH peak (<5 ng/ml), 27 demonstrated a normal response (>10 ng/ml) and 9 showed an intermediate rise in plasma GH (5–10 ng/ml). Six of the 12 patients with low GH response to the first GHRH stimulation failed to respond to two other tests immediately before and after a 1 week priming with s.c. GHRH. These subjects with subnormal GH increase at repeat testing had total GHD (TGHD) and multiple pituitary hormone deficiency (MPHD) and had suffered from perinatal distress. On the contrary, 26 of 27 patients with normal GH response to the first test had isolated GHD and only a minority (8/27) had signs of perinatal distress. It is concluded that perinatal injuries primarily damage pituitary structures and that a pituitary defect more probably underlies more severe forms (TGHD and MPHD) of GHD.

Metabolic Outcomes, Bone Health, and Risk of Polycystic Ovary Syndrome in Girls with Idiopathic Central Precocious Puberty Treated with Gonadotropin-Releasing Hormone Analogues

Background/Aims: Gonadotropin-releasing hormone analogues (GnRHa) represent the gold standard treatment for central precocious puberty (CPP). We aimed to assess the effects of GnRHa treatment on metabolic outcomes, bone status, and polycystic ovary syndrome (PCOS) prevalence in young girls with idiopathic CPP (ICPP). Methods: We enrolled 94 ICPP girls who were at least 2 years after menarche and had already attained adult height at the time of the study: 56 previously treated with depot triptorelin (3.4 ± 0.6 years) and 38 untreated. Auxological parameters, lipid profile, homeostatic model assessment of insulin resistance (HOMA-IR), bone state, and prevalence of PCOS were assessed. Results: The 2 groups were similar for body mass index (BMI) and waist circumference. HOMA-IR, dehydroepiandrosterone sulfate, and Δ4-androstenedione were higher in the treated than in the untreated subjects (p < 0.001). Significant differences were found for amplitude-dependent speed of sound (p < 0.03) and bone transmission time z-scores (p < 0.01). The prevalence of PCOS was higher in the treated than in the untreated subjects (p < 0.04). Conclusion: GnRHa therapy is associated with hyperandrogenism and an increase in insulin resistance and PCOS prevalence, but not with increased BMI or lipid profile alterations. Long-term evaluations at the time of expected peak bone mass achievement are needed to understand the persistent or transient nature of subtle bone abnormalities.