Ketoacidosis at diagnosis in childhood-onset diabetes and the risk of retinopathy 20years later.

AIMS: To investigate on the relationship between severity of ketoacidosis, an important risk factor for C-peptide preservation, and long-term microvascular complications in childhood-onset type 1 diabetes mellitus (T1DM). METHODS: 230 childhood-onset diabetic patients (177 pre-pubertal), aged 7.0±3.8years followed for at least 15years after their diagnosis, were enrolled. Clinical and laboratory data at diagnosis, and C-peptide levels in a subset of patients, were compared with the severity of retinopathy and nephropathy, after a mean of 19.6±3.8years of disease. Digital retinal photographs were taken in all patients, and centrally graded. Repeated measurements of HbA1c and microalbuminuria for the whole duration of diabetes were collected in over half of the cases. RESULTS: Out of 230 patients, those with the lowest age at diagnosis had the most severe DKA and clinical conditions (p<0.05), and lower C-peptide levels (p<0.0001) at diagnosis. There was a significant relationship between pH and clinical severity (r=-0.783, p<0.0001), and between pH and C-peptide levels (r=0.278, p<0.05). The severity of ketoacidosis had no relationship with subsequent lifetime HbA1c values and long-term microvascular complications. In logistic regression analysis, the only variables that independently influenced severity of retinopathy were lifetime HbA1c (B=0.838, p<0.001), duration of disease (B=0.208, p<0.005) and age at diagnosis (B=0.116, p<0.05). CONCLUSIONS: The degree of metabolic derangement at diagnosis is not associated with retinopathy and nephropathy in childhood-onset T1DM. Age at diagnosis seems to be an important variable to be considered when evaluating the long-term effects of residual beta-cell function.

Infant and toddler type 1 diabetes: complications after 20 years' duration.

OBJECTIVE: To compare the effect of the prepubertal duration of diabetes on the occurrence of complications in two groups of patients after the same number of years of the disease. RESEARCH DESIGN AND METHODS: This multicenter study enrolled 105 patients aged 16-40.3 years; 53 were prepubertal at diagnosis (aged 0-3) and 52 were pubertal (Tanner stage) and aged 9-14.9. The mean duration of disease was 19.8 and 19.5 years for prepubertal and pubertal patients, respectively. In all patients, retinal photographs were taken and centrally graded. Urinary albumin excretion (UAE; 86 case subjects), blood pressure (BP; 89 case subjects), and lifetime HbA(1c) (72 case subjects) were also evaluated. RESULTS: The prevalence of diabetic retinopathy (DR) was higher in pubertal than in prepubertal patients, both for any grade DR (71 vs. 40%, P = 0.002) and for mild or more severe DR (P = 0.005). The prevalence of abnormal UAE was not different in the two groups. Hypertension was found only in three patients, all pubertal at diagnosis. In the small group with moderate-to-severe DR, lifetime HbA(1c) levels, as percentages above the upper normal reference value, were higher (P < 0.01) in prepubertal than in pubertal patients. CONCLUSIONS: If diabetes is diagnosed in infants or toddlers and the prepubertal duration of diabetes is very long, the patients seem to be protected against DR. This protection disappears if lifetime metabolic control is bad. Instead, when onset is at puberty, the DR risk is higher and less dependent on metabolic control and may be influenced by age-related factors, such as BP.

Cut-off limits of the GH response to GHRH plus arginine test and IGF-I levels for the diagnosis of GH deficiency in late adolescents and young adults.

OBJECTIVE: To define the appropriate diagnostic cut-off limits for the GH response to GHRH+arginine (ARG) test and IGF-I levels, using receiver operating characteristics (ROC) curve analysis, in late adolescents and young adults. DESIGN AND METHODS: We studied 152 patients with childhood-onset organic hypothalamic-pituitary disease (85 males, age (mean+/-s.e.m.): 19.2+/-0.2 years) and 201 normal adolescents as controls (96 males, age: 20.7+/-0.2 years). Patients were divided into three subgroups on the basis of the number of the other pituitary hormone deficits, excluding GH deficiency (GHD): subgroup A consisted of 35 panhypopituitary patients (17 males, age: 21.2+/-0.4 years), subgroup B consisted of 18 patients with only one or with no more than two pituitary hormone deficits (7 males, age: 20.2+/-0.9 years); and subgroup C consisted of 99 patients without any known hormonal pituitary deficits (60 males, age: 18.2+/-0.2 years). Both patients and controls were lean (body mass index, BMI<25 kg/m(2)). Patients in subgroup A were assumed to be GHD, whereas in patients belonging to subgroups B and C the presence of GHD had to be verified. RESULTS: For the GHRH+ARG test, the best pair of highest sensitivity (Se; 100%) and specificity (Sp; 97%) was found choosing a peak GH of 19.0 microg/l. For IGF-I levels, the best pair of highest Se (96.6%) and Sp (74.6%) was found using a cut-off point of 160 microg/l (SDS: -1.3). Assuming 19.0 microg/l to be the cut-off point established for GHRH+ARG test, 72.2% of patients in subgroup B and 39.4% in subgroup C were defined as GHD. In patients belonging to group B and C and with a peak GH response <19 microg/l to the test, IGF-I levels were lower than 160 microg/l (or less than 1.3 SDS) in 68.7 and 41.6% of patients respectively predicting severe GHD in 85.7% of panhypopituitary patients (subgroup A). CONCLUSIONS: In late adolescent and early adulthood patients, a GH cut-off limit using the GHRH+ARG test lower than 19.0 microg/l is able to discriminate patients with a suspicion of GHD and does not vary from infancy to early adulthood.

Traumatic brain injury and hypopituitarism in children and adolescents: is the problem under-estimated?

Traumatic brain injury (TBI) is the leading cause of death in children. Only recently, the importance of hypopituitarism as a consequence of TBI has been highlighted in adult patients. Data from systematic clinical studies in adults and patients in transition from adolescence to adulthood point to the presence of hypopituitarism in nearly a third of patients hospitalized for TBI. But, no systematic studies on posttraumatic hypopituitarism exist in children and adolescents. Case reports and small series of patients, however, suggest that children are affected to a comparable extent. Since normal pituitary function is required for normal growth and pubertal development in childhood, particular attention should be paid to this condition. The aim of this review is to summarize the literature on TBI and causes, clinical picture, and diagnosis of hypopituitarism in childhood and adolescence, underlying the relevance of the problem and its underestimation in clinical paediatric practice.

Residual pituitary function after brain injury-induced hypopituitarism: a prospective 12-month study.

CONTEXT: Traumatic brain injury (TBI) and subarachnoid hemorrhage (SAH) are conditions at high risk for the development of hypopituitarism. OBJECTIVE: The objective of the study was to clarify whether pituitary deficiencies and normal pituitary function recorded at 3 months would improve or worsen at 12 months after the brain injury. DESIGN AND PATIENTS: Pituitary function was tested at 3 and 12 months in patients who had TBI (n = 70) or SAH (n = 32). RESULTS: In TBI, the 3-month evaluation had shown hypopituitarism (H) in 32.8%. Panhypopituitarism (PH), multiple (MH), and isolated (IH) hypopituitarism had been demonstrated in 5.7, 5.7, and 21.4%, respectively. The retesting demonstrated some degree of H in 22.7%. PH, MH, and IH were present in 5.7, 4.2, and 12.8%, respectively. PH was always confirmed at 12 months, whereas MH and IH were confirmed in 25% only. In 5.5% of TBI with no deficit at 3 months, IH was recorded at retesting. In 13.3% of TBI with IH at 3 months, MH was demonstrated at 12-month retesting. In SAH, the 3-month evaluation had shown H in 46.8%. MH and IH had been demonstrated in 6.2 and 40.6%, respectively. The retesting demonstrated H in 37.5%. MH and IH were present in 6.2 and 31.3%, respectively. Although no MH was confirmed at 12 months, two patients with IH at 3 months showed MH at retesting; 30.7% of SAH with IH at 3 months displayed normal pituitary function at retesting. In SAH, normal pituitary function was always confirmed. In TBI and SAH, the most common deficit was always severe GH deficiency. CONCLUSION: There is high risk for H in TBI and SAH patients. Early diagnosis of PH is always confirmed in the long term. Pituitary function in brain-injured patients may improve over time but, although rarely, may also worsen. Thus, brain-injured patients must undergo neuroendocrine follow-up over time.

The cut-off limits of the GH response to GH-releasing hormone-arginine test related to body mass index.

OBJECTIVE: The diagnosis of growth hormone (GH) deficiency (GHD) in adults is based on a reduced peak GH response to provocative tests, such as the insulin tolerance test (ITT) and the GH-releasing hormone-arginine (GHRH-ARG) test. However, the cut-off limits of peak GH response in lean subjects are not reliable in obese patients; this is noteworthy since adult GHD is often associated with obesity. Aim of this study was to evaluate the diagnostic cut-off limits of peak GH response to the GHRH-ARG test in overweight and obese as well as in lean population. DESIGN AND METHODS: The GH responses to the GHRH-ARG test were studied in 322 patients with organic hypothalamic-pituitary disease and in 318 control subjects. Patients were subdivided into two groups on the basis of the number of pituitary hormone deficits, except for GH deficiency: (a) patients with total pituitary hormone deficit (TPHD) and (b) patients without or with no more than two pituitary hormone deficits (PHD). Both patients and control subjects were divided into three subgroups according to body mass index (BMI): lean (BMI <25 kg/m(2)), overweight (BMI > or = 25 and <30 kg/m(2)) and obese (BMI > or =30 kg/m(2)). TPHD patients were assumed to be GH deficient, whereas PHD patients may include subjects with either normal or impaired GH secretion. The statistical analysis was carried out by the Receiver-Operating Characteristic curve analysis (Medcalc 7.2). The diagnostic cut-off points were calculated for lean, overweight and obese subjects to provide optimal separation of GH-deficient patients and control subjects according to two criteria: (1) a balance between high sensitivity and high specificity; (2) to provide the highest pair of sensitivity/specificity values for GH deficiency. RESULTS: In the lean population the best pair of values, with highest sensitivity as 98.7% and highest specificity as 83.7%, was found using a peak GH cut-off point of 11.5 mug/l. In the overweight population the best pair of values, 96.7 and 75.5%, respectively, was found using a peak GH cut-off point of 8.0 mug/l. In the obese population the best pair of values, 93.5 and 78.3%, respectively, was found using a peak GH cut-off point of 4.2 mug/l. Applying the above mentioned cut-off points, among PHD patients we found that 80 subjects (72%) were GHD whereas 31 (28%) had normal GH secretion. CONCLUSIONS: In conclusion the GHRH-ARG test is a reliable tool for the diagnosis of adult GH deficiency in lean, overweight and obese patients, provided that specific BMI-related cut-off limits are assumed.

IGFs and IGFBPs in adult growth hormone deficiency.

In the current guidelines for the diagnosis of adult GH deficiency (GHD) it is stated that, within the appropriate clinical context, it has to be shown by provocative tests only. But the diagnostic value of measuring IGF-I levels has been recently revisited. It has been confirmed that normal IGF-I levels do not rule out severe GHD in adults. However, it has also been emphasized that very low IGF-I levels in patients highly suspected for GHD (and without malnutrition, liver disease or hypothyroidism) could be considered definite evidence for severe GHD. This assumption particularly applies to patients with childhood-onset, severe GHD or with multiple hypopituitarism acquired in adulthood. The value of measuring IGF-I levels for monitoring the efficacy and the adequacy of rhGH replacement remains definitely accepted.

Insulin-like growth factor I levels and the diagnosis of adult growth hormone deficiency.

The current guidelines state that, within the appropriate clinical context, the diagnosis of adult growth hormone (GH) deficiency must be made biochemically using provocative tests. Measurement of insulin-like growth factor I (IGF-I) and binding protein 3 (IGFBP-3) levels cannot always distinguish between healthy and GH-deficient individuals. In particular, IGFBP-3 as a marker of GH status is clearly less sensitive than IGF-I and there is general agreement that its measurement does not provide useful diagnostic information. However, the diagnostic value of measuring IGF-I levels has been revisited recently. It has been confirmed that normal IGF-I levels do not rule out severe GH deficiency (GHD) in adults, in whom the diagnosis has therefore to be based on the demonstration of severe impairment of the peak GH response to provocative tests. It has also been emphasized that very low IGF-I levels in patients with high suspicion of GHD could be considered to be definite evidence for severe GHD. This assumption particularly applies to patients with childhood-onset, severe GHD or with multiple hypopituitary deficiencies acquired in adulthood. In addition, the use of IGF-I levels to monitor the efficacy and adequacy of recombinant human GH replacement remains widely accepted.

GHRH and GH secretagogues: clinical perspectives and safety.

The diagnosis and treatment of growth hormone deficiency (GHD), as well as the possibility of counteracting somatopause and age-related changes in body composition, structural functions, and metabolism, prompted interest in potential clinical uses of GH-releasing hormone (GHRH) and GH secretagogues (GHS). GHD often reflects hypothalamic GHRH deficiency and it has been clearly demonstrated that the age-related decline in the function of the GH/IGF-I axis reflects a reduction in hypothalamic function as evidenced by the preservation of the releasable pool of pituitary GH in aged subjects. The effectiveness of recombinant human GH (rhGH) is well established, but it is also recognized that GH replacement does not mimic physiological GH secretion which theoretically would be restored by GHRH and/or GHS. At present, it has been clearly demonstrated that GHRH and/or GHS represent reliable tools for the diagnosis of GHD. On the other hand, neither GHRH nor GHS has been shown to provide effective alternatives to rhGH for the treatment of GHD. Although GHRH and/or GHS represent the most logical approaches for the restoration of the GH/IGF-I axis to a youthful level of activity and for counteracting the somatopause, this hypothesis has never been proven definitively. Conceptually, GHRH replacement would be the most physiological approach and its safety is guaranteed, provided an appropriate dose is used, in order to avoid hyperactivity of the GH/IGF-I axis. However, a long-acting preparation is needed. On the other hand, GHS, e.g., ghrelin analogues, could be considered as a function of their selectivity of action. However, ghrelin has a wide spectrum of endocrine and non-endocrine actions at both central and peripheral levels. Thus, non-selective GHS, although available in orally active forms, could elicit unforeseen side effects. Previous studies with GHRH and/or GHS in aging patients provided encouraging results. However, it still remains to be definitively demonstrated that aged subjects would benefit from chronic treatment with these molecules.