UNIPROT:P01275 - FACTA Search

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Query: UNIPROT:P01275 (glucagon)
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To establish the diagnosis of adult growth hormone deficiency (GHD), GH-deficient children transitioning to adulthood are evaluated by two separate stimuli 2 or more weeks after ceasing GH therapy. While 20-88% of children diagnosed with idiopathic GHD retest with normal values, those with proven genetic defects in GH production/secretion/bioactivity and patients with panhypopituitarism consistently test deficient. The US Food and Drug Administration (FDA) defines GHD in adults by stimulated peak serum GH concentrations <5 ng/ml if measured by polyclonal radioimmunoassays (RIA) or lower if measured by monoclonal assays. Some investigators define severe GHD by a peak GH concentration <3 ng/ml. Adult responses to arginine and glucagon testing are similar to the responses to insulin tolerance testing; clonidine, pyridostigmine, and galanin cause lesser peaks of GH. Growth hormone-releasing hormone (GHRH) combined with arginine, GH releasing peptide-6 (GHRP-6), or hexarelin leads to higher peak responses than GHRH alone. Thus the choice of testing methods impacts the diagnosis of GHD in transition patients.
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PMID:A practical approach to the diagnosis of growth hormone (GH) deficiency in patients transitioning to adulthood using GH stimulation testing. 1279 66

The accurate assessment of adrenal function is necessary in many children with suspicion of pituitary insufficiency. The objective of this study was to evaluate the adrenal response during the glucagon stimulation test (GST) and its diagnostic utility in children. A total of 290 children, aged 10.1 +/- 5.0 years, were evaluated for adrenal function using the corticotrophin releasing hormone (CRH) test, the GST, and/or the insulin tolerance test (ITT). Glucagon stimulation provoked a substantial rise in cortisol and adrenocorticotropin (ACTH) that was independent of gender, age, or underlying growth hormone deficiency. There were no differences in peak cortisol levels in the GST compared to the CRH test in pair-wise intra-individual analyses in children with both tests performed within one year (615.4 +/- 30.5 vs 602.8 +/- 22.4 nmol/l, n=52). Similarly, there were no differences in the cortisol response between the ITT and CRH test. Peak cortisol levels in the CRH test correlated with the GST and the ITT. The magnitude of ACTH response, in contrast, was highest in the ITT with a 9.8-fold increase over baseline, while the increase in the GST (3.1-fold) and CRH test (1.6-fold) were more subtle. Since there is controversy concerning reliable cut-off values for adrenal function tests in children, we analyzed cut off levels in 186 children, including 26 children with adrenal insufficiency, using the CRH test. A peak cortisol level of 450 nmol/l provided the best balance of sensitivity (88.5%) and specificity (86.8%), while higher cut-off levels did not increase sensitivity but lost in specificity. In summary, the GST constitutes an1 equally sensitive test for the assessment of adrenal function in children that is not confounded by anthropometric parameters and is generally not accompanied by major side effects. It allows the simultaneous assessment of corticotroph and somatotroph function and may thus constitute a valuable alternative to the ITT.
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PMID:Comparison of adrenal function tests in children--the glucagon stimulation test allows the simultaneous assessment of adrenal function and growth hormone response in children. 1592 Nov 71

Although paediatric Cushing's disease is rare, it is associated with severe morbidity in childhood and presents a major diagnostic and therapeutic challenge for the paediatric endocrinologist. Growth failure remains an important feature of paediatric Cushing's disease, both at diagnosis and after successful treatment. However, the development of specific diagnostic tests and important therapeutic advances has contributed significantly to the current management. Transsphenoidal pituitary surgery (TSS) is now accepted as first-line therapy for both adult and paediatric Cushing's disease, offering the best opportunity for cure while preserving normal pituitary function. The cure rate following TSS in our centre is currently 62%; therefore, a significant proportion of children following TSS will remain uncured. Our favoured second-line therapy is pituitary radiotherapy, which is effective, rapid and appears to spare anterior pituitary function, with the exception of GH secretion. Growth failure was a symptom at diagnosis in 74% of patients; mean height SDS -1.81 (-0.28 to -4.17) compared with mean BMI SDS 2.29 (1.72-5.06). Height velocity (HV) was also subnormal; range 0.9-3.8 cm/yr. Chronic hypercortisolaemia suppresses linear growth and a history of symptoms for >2 years was obtained in 72% of our paediatric patients with Cushing's disease. In our series, 9 out of 10 patients did not demonstrate catch-up growth 0.64 years after TSS or pituitary radiotherapy and peak serum GH level to glucagon/ITT stimulation was 0.5-20.9 mU/l. Assessment of GH secretion over a period of 6 to 108 months after cure of paediatric Cushing's disease suggests that impaired GH secretion may persist into adult life. Investigation of possible GHD is performed in our unit in all post-cure patients who do not show optimal catch-up growth. If GH secretion is subnormal, GH replacement is started early and continued until final height, when GH secretion is reassessed. In our series of 10 patients, 9 received GH therapy, combined in 3 with a GnRH analogue to arrest puberty. The results of this treatment were satisfactory with mean height deficit compared with target height improving significantly from mean -1.72 +/- 1.26 SDS at diagnosis to -0.93 +/- 1.13 SDS (p=0.005) at final height or latest assessment, indicating that a favourable final height can be achieved.
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PMID:Growth and growth hormone secretion in paediatric Cushing's disease. 1700 7

Current guidelines for the diagnosis of adult growth hormone deficiency (GHD) state that the diagnosis must be proven biochemically by provocative testing that is done within the appropriate clinical context. The need for reliance on provocative testing is based on evidence that the evaluation of spontaneous growth hormone (GH) secretion over 24 h and the measurement of IGF-I and IGFBP-3 levels do not distinguish between normal and GHD subjects. Regarding IGF-I, it has been demonstrated that very low levels in patients highly suspected for GHD (i.e., patients with childhood-onset, severe GHD, or with multiple hypopituitarism acquired in adulthood) may be considered definitive evidence for severe GHD obviating the need for provocative tests. However, normal IGF-I levels do not rule out severe GHD and therefore adults suspected for GHD and with normal IGF-I levels must undergo a provocative test of GH secretion. The insulin tolerance test (ITT) is the test of choice, with severe GHD being defined by a GH peak less than 3 microg/l, the cut-off that distinguishes normal from GHD adults. The ITT is contraindicated in the presence of ischemic heart disease, seizure disorders, and in the elderly. Other tests are as reliable as the ITT, provided they are used with appropriate cut-off limits. Glucagon stimulation, a classical test, and especially new maximal tests such as GHRH in combination with arginine or GHS (i.e., GHRP-6) have well-defined cut-off limits, are reproducible, are independent of age and gender, and are able to distinguish between normal and GHD subjects. The confounding effect of overweight or obesity on the interpretation of the GH response to provocative tests needs to be considered as the somatotropic response to all stimuli is negatively correlated with body mass index. Appropriate cut-offs for lean, overweight, and obese subjects must be used in order to avoid false-positive diagnoses of severe GHD in obese adults.
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PMID:Growth hormone levels in the diagnosis of growth hormone deficiency in adulthood. 1742 91

The current guidelines for the diagnosis of adult GHD are mainly based on the statements from the GH Research Society Consensus from Port Stevens in 1997. It is stated that diagnosis of adult GHD must be shown biochemically by provocative tests within the appropriate clinical context. The insulin tolerance test (ITT) was indicated as that of choice and severe GHD defined by a GH peak lower than 3 microg/L. The need to rely on provocative tests is based on evidence that that the measurement of IGF-I as well as of IGFBP-3 levels does not distinguish between normal and GHD subjects. Hypoglycemia may be contraindicated; thus, alternative provocative tests were considered, provided they are used with appropriate cut-off limits. Among classical provocative tests, arginine and glucagon alone were indicated as alternative tests, although less discriminatory than ITT. Testing with the combined administration of GHRH plus arginine was recommended as an alternative to ITT, mostly taking into account its marked specificity. Based on data in the literature in the last decade, the GRS Consensus Statements should be appropriately amended. Regarding the appropriate clinical context for the suspicion of adult GHD, one should evaluate patients with hypothalamic or pituitary disease or a history of cranial irradiation, as well as those with childhood-onset GHD are at obvious risk as adults for severe GHD. Brain injuries (trauma, subarachnoid hemorrage, tumours of the central nervous system) very often cause acquired hypopituitarism, including severe GHD. Given the epidemiology of brain injuries, the important role of the endocrinologist in providing major clinical benefit to brain injured patients who are still undiagnosed should be underscored. From the biochemical point of view, although normal IGF-I levels do not rule out severe GHD, very low IGF-I levels in patients highly suspected for GHD (i.e. patients with childhood-onset, severe GHD or with multiple hypopituitarism acquired in adulthood) can be considered as definitive evidence for severe GHD; thus, these patients would skip provocative tests. Patients suspected for adult GHD with normal IGF-I levels must be investigated by provocative tests. ITT remains a test of reference but it should be recognized that other tests are as reliable as ITT. Glucagon as classical test and, particularly, new maximal tests such as GHRH in combination with arginine or GH secretagogues (GHS) (i.e. GHRP-6) have well defined cut-off limits, are reproducible, able to distinguish between normal and GHD subjects. Overweight and obesity have confounding effect on the interpretation of the GH response to provocative tests. In adults cut-off levels of GH response below which severe GHD is demonstrated must be appropriate to lean, overweight and obese subjects to avoid false positive diagnosis in obese adults and false negative diagnosis in lean GHD patients. Finally, normative values of GH response to provocative tests may depend on age, particularly in the transitional age; the normative cut-off levels of GH response to ITT in this phase of life are now available.
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PMID:Diagnosis of adult GH deficiency. 1776 55

Based on previous consensus statements, it has been widely accepted that the diagnosis of adult growth hormone deficiency (GHD) must be shown biochemically by provocative tests of GH secretion; in fact, the measurement of IGF-I as well as of other markers was considered unable to distinguish between normal and GHD subjects. The Insulin Tolerance Test (ITT) was indicated as that of choice and severe GHD defined by a GH peak lower than 3 microg/l. It is now recognized that, although normal IGF-I levels do not rule out severe GHD, very low IGF-I levels in patients highly suspected for GHD (i.e. patients with childhood-onset severe GHD or with multiple hypopituitarism acquired in adulthood) can be considered as definite evidence for severe GHD. However, patients suspected for adult GHD with normal IGF-I levels must be investigated by provocative tests. ITT remains a test of reference but it should be recognized that other tests are as reliable as ITT. Glucagon as classical test and, particularly, new maximal tests such as GHRH in combination with arginine or GH secretagogues (GHS) (i.e. GHRP-6) have well defined cut-off limits, are reproducible, able to distinguish between normal and GHD subjects. Overweight and obesity have confounding effect on the interpretation of the GH response to provocative tests. In adults cut-off levels of GH response below which severe GHD is demonstrated must be appropriate to lean, overweight and obese subjects to avoid false positive diagnosis in obese adults and false negative diagnosis in lean GHD patients.
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PMID:Diagnosis of adult GH deficiency. 1840 87

The diagnosis of growth hormone (GH) deficiency (GHD) is still problematic for the clinician. There is no gold standard for estimating GH secretion. The aim of this study was to compare the diagnostic usefulness of spontaneous GH secretion test, pharmacological tests with insulin, clonidine, L-dopa, and glucagon, and IGF-I measurement in GHD. We studied 180 prepubertal, short children. Predictive values were calculated for different GH cutoff levels for each diagnostic test. ROC curves were used to estimate the diagnostic usefulness of the tests. The results show that sleep is the strongest stimulatory agent for GH secretion. The estimation of GH secretion after onset of sleep can be used as a screening test in GHD diagnosis. The insulin test has the highest discrimination. A combination of insulin test with another provocative test allows high discrimination and accuracy for standard cut-off GH level. Measurement of IGF-I is characterized by low predictive values. IGF-I level below the mean according to age indicates high probability of GHD. Auxological parameters should be the most important factor in diagnosing GHD.
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PMID:Usefulness of growth hormone (GH) stimulation tests and IGF-I concentration measurement in GH deficiency diagnosis. 1871 43

Johanson-Blizzard syndrome (JBS) is a rare autosomal recessive condition associated with exocrine pancreatic insufficiency, and is characterized by hypoplastic nasal alae, mental retardation, sensorineural hearing loss, short stature, scalp defects, dental abnormalities and abnormal hair patterns. Growth hormone deficiency, hypopituitarism, and impaired glucagon secretion response to insulin-induced hypoglycemia have been reported. Congenital heart defects have also been described in this condition. Mental retardation is typically moderate to severe in patients with JBS; however, normal intelligence can occur. In the pancreas, there is a selective defect of acinar tissue, whereas the islets of Langerhans and ducts are preserved. Diabetes has been reported in older children, suggesting the progressive nature of pancreatic disease. The molecular basis of JBS has recently been mapped to chromosome 15q15-q21 with identified mutations in the UBR1 gene. We report the case of a 7-year-old female with pancreatic insufficiency and mild phenotypic features, in whom the diagnosis of JBS was established using recently described molecular testing for the UBR1 gene.
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PMID:Johanson-Blizzard syndrome with mild phenotypic features confirmed by UBR1 gene testing. 1905 15

Adult growth hormone deficiency (aGHD) has been widely accepted in endocrinological practice. The primary cause of aGHD has been considered to be hypothalamic-pituitary lesions. Traumatic brain injury and subarachnoid hemorrhage have, however, been emerging as important etiologies of aGHD in recent years. Considering the high incidences of these brain injuries and significant rate of hypopituitarism in the survivors, the impact of aGHD on public health should be much larger than it is generally considered. Patients with aGHD may present with reduced lean body mass, increased body adiposity, reduced muscle strength and exercise capacity, thin and dry skin, cool, peripheries and impaired psychological well-being. The peak GH level should be under 3ng/mL when tested by the insulin tolerance, arginine, L-DOPA, or glucagon tests in aGHD patients. The peak GH value should be under 9 ng/mL when tested by the GHRP-2 test, this test is currently available only in Japan, and is a safe and quick method to assess the GH secretory function. A low level of IGF-1 may be an indicator of GHD in the presence of hypopituitarism, but a normal IGF-I does not rule out GHD. The GH replacement dose should be adjusted according to the normal physiology in order to minimize the risk of side effects. GH replacement may influence the metabolism of thyroid, glucocorticoid hormone, and increase the requirement of hormones. Long-term GH replacement therapy has been reported to improve the morbidity and moratlity of aGHD. Although there is no evidence to prove that GH replacement increases the risk of recurrence of tumor, de-novo neoplasm, or serious cardiovascular disease, the long-term safety of GH replacement should be rigorously monitored.
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PMID:[Diagnosis and treatment of adult growth hormone deficiency (aGHD) resulting from brain injury--role of aGHD]. 1911 Jul 56

An 8-week-old infant presented to the emergency department with lethargy, tachycardia, and a blood glucose concentration of 1.8 mmol/L. After admission, hypoglycemia recurred on 3 additional occasions. Initial urinalysis results were negative for ketones, and the results of additional laboratory tests did not support the diagnosis of cortisol or growth hormone deficiency, oral hypoglycemic ingestion, or an inborn error of metabolism. Difficulty restoring and maintaining glucose concentrations along with a transient response to glucagon during 1 hypoglycemic episode suggested hyperinsulinism. In 1 hypoglycemic episode, elevated insulin and low C-peptide concentrations suggested exogenous insulin administration, but 2 subsequent blood samples obtained during hypoglycemia contained appropriately decreased concentrations of insulin. The insulin immunoassay initially used in this case (Roche ElecSys/cobas [Roche Diagnostics, Indianapolis, IN]) was insensitive to insulin analogs. Two additional immunoassays, 1 with intermediate (Immulite [Siemens, Deerfield, IL]) and 1 with broad (radioimmunoassay [Millipore, Inc, Billerica, MA]) reactivity to insulin analogs were used to characterize insulin in each of the critical blood samples. Samples obtained during hypoglycemia displayed a graded reactivity similar to that observed in type 1 diabetic patients prescribed insulin analogs, whereas a sample obtained from the patient and a control subject during euglycemia showed equal reactivity among the 3 assays. These data suggested administration of insulin analog to the child, and further characterization of insulin by using tandem mass spectrometry confirmed the presence of Humalog. The child was subsequently placed in foster care with no further recurrence of hypoglycemia.
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PMID:Detection of surreptitious administration of analog insulin to an 8-week-old infant. 2038 35

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