Silvia Rovere

Diagnostic reliability of a single IGF-I measurement in 237 adults with total anterior hypopituitarism and severe GH deficiency

objective Within an appropriate clinical context, GH deficiency (GHD) in adults must be demonstrated biochemically by a single provocative test. Insulin‐induced hypoglycaemia (ITT) and GH‐releasing hormone (GHRH) + arginine (ARG) are indicated as the tests of choice, provided that appropriate cut‐off limits are defined. Although IGF‐I is the best marker of GH secretory status, its measurement is not considered a reliable diagnostic tool. In fact, considerable overlap between GHD and normal subjects is present, at least when patients with suspected GHD are considered independently of the existence of other anterior pituitary defects. Considering the time and cost associated with provocative testing procedures, we aimed to re‐evaluate the diagnostic power of IGF‐I measurement.

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.

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.

Occurrence of GH deficiency in adult patients who underwent neurosurgery in the hypothalamus–pituitary area for non-functioning tumour masses

Hypothalamus-pituitary tumours and their treatments (neurosurgery and/or radiotherapy) are major causes of acquired hypopituitarism. Scientific and clinical evidences show the positive effect of GH replacement therapy in severe adult GH deficiency (GHD) pointed toward the need of diagnostic screening of conditions at high risk for GHD. We screened 152 adults (82 males, 70 females; age: 52.3+/-1.2 years, age-range: 20-80 years, BMI: 26.4+/-0.8 kg/m(2)) in order to disclose the presence of GHD after neurosurgery for hypothalamus-pituitary tumours. The whole group (studied at least 3 months after neurosurgery) included: 111 non-functioning pituitary adenomas and 41 peri-pituitary tumours (24 craniopharyngiomas, 7 meningiomas, 5 cysts, 2 chondrosarcomas, 1 colesteatoma, 1 germinoma and 1 hemangiopericitoma). In 14 patients who underwent both neurosurgery and radiotherapy due to a tumour remnant, the somatotroph function was evaluated again 6 months after the end of radiotherapy. GHD was assumed to be shown by GH peak <5 microg/L (severe <3 microg/L) after Insulin Tolerance Test (ITT) or <16.5 microg/L (severe <9 microg/L) after GH-releasing hormone+arginine test (GHRH+ARG) (3rd and 1st centile limits of normality, respectively), two widely accepted provocative tests. Before neurosurgery GHD was present in 97/152 (63.8%) and resulted severe in 66/152 (43.4%) patients. After neurosurgery GHD was present in 122/152 (80.2%) and severe in 106/152 (69.7%). While 26 patients developed severe GHD (GHD) as consequence of neurosurgery, only one patient who had been classified as GHD before neurosurgery showed normal GH response after surgery. After neurosurgery, 91.0% (81/89) of the pan-hypopituitaric patients showed severe GHD. Considering the 14 patients who underwent also radiotherapy after neurosurgery, 7/14 had GHD before neurosurgery while 12/14 became severe GHD after radiotherapy in a context of pan-hypopituitarism. IGF-I levels below the 3rd age-related normal limits were present in 39.0% of patients in whom severe GHD was showed by provocative tests. In conclusion, this study shows that the occurrence of acquired severe GHD is extremely common in adult patients bearing non-functioning tumour masses in the hypothalamus-pituitary area and further increases after neurosurgery. All patients bearing non-functioning hypothalamus-pituitary tumours should undergo evaluation of their somatotroph function before and after neurosurgery that represents a condition at obvious more than high risk for hypopituitarism.

Short procedure of GHRH plus arginine test in clinical practice

Either in children or in adults, arginine (ARG) alone and combined with GHRH (GHRH + ARG) are reliable tests for the diagnosis of GH deficiency. The procedures of these tests generally include GH measurement every 15 min from baseline up to 90–120 min. Aim of our study was to verify if the procedure of these tests could be usefully shortened in clinical practice. To this goal we have studied 173 normally growing children and adolescents (C, 117 M and 56 F, age: 11.3 ± 0.4 yr.) and 125 young and middle aged normal adults (A, 68 M and 57 F, age: 30.0 ± 0.6 yr.). ARG alone test was performed by 81 C and 33 A (0.5 g/kg arginine, iv, from 0 to +30 min, up to a maximum of 30 g) while GHRH (1 μg/kg iv bolus at 0 min) + ARG test was performed by 92 C and 92 A. After ARG alone, taking into account data from +15 to +105 min, GH values above the 3rd centile limit of arbitrary cut-off (7 or 10 μg/1 in C and 5 μg/1 in A) occurred in 85% or 64% and 94% subjects, respectively. After GHRH + ARG test, taking into account only data at +30, +45, +60 min GH values above the 3rd centile limit (20 μg/1 in C and 16.5 μg/1 in A) occurred in 99% of subjects in both groups. Taking into account only these 3 timing points, the percentage of GH peak above the third centile limits after ARG alone was never higher than 60% in C and 85% in A. In conclusion, this study shows that single GHRH + arginine test can be reliably performed in a shortened procedure which makes easier the clinical practice and further reduces costs.

Different degrees of GH deficiency evidenced by GHRH+arginine test and IGF-I levels in adults with pituritary disease.

To verify if the entity of the peak GH responses to the GHRH+arginine (ARG) test is able to show different degree forms of GH deficiency (GHD), we linked these responses with the number of other anterior pituitary deficits. These anterior pituitary deficits were also related with IGF-I levels. To this purpose, we studied a large cohort of lean patients with pituitary disease of different etiologies [86 males and 68 females; age: mean±SEM 41.5±1.2 yr, body mass index (BMI) <25 kg/m2]. The patients were subdivided into 4 groups according to the increasing number of hormone deficiencies: isolated GHD (HYPO1, no.=28) or GHD plus one, two or three additional hormones (gonadotrophin, ACTH, and TSH) deficiencies (HYPO2, no.=20; HYPO3, no.=15; HYPO4, no.=91). Peak GH responses to the GHRH+ARG test and IGF-I levels showed a clear difference among the groups (p<0.01 and p<0.001, respectively). A significant difference was found between HYPO1 and HYPO4 for IGF-I levels (p<0.05), and between HYPO1 and HYPO4 and between HYPO2 and HYPO4 for the GHRH+ARG test (p<0.005). Considering only the patients who underwent both GHRH+ARG test and insulin tolerance test (ITT) (no.=70), the pattern of the peak GH responses to the GHRH+ARG test was the same of the whole group of patients, while no statistical difference was found with ITT. Our data show that the peak GH responses to the GHRH+ARG test and the IGF-I levels are linked to the severity of hypopituitarism, expressed by the number of increasing anterior pituitary deficits. This association is lost if the evaluation of the GH status is performed by the ITT. In all, the GHRH+ARG test and measurement of IGF-I are able to evidence different degrees of GHD in adult patients with pituitary disease.

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.

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 mellitus: 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 HbA1c (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 HbA1c 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.

Infant and Toddler Type 1 Diabetes

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 HbA1c (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 HbA1c 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.