Adipocytes as a source of increased circulating levels of nicotinamide phosphoribosyltransferase/visfatin in active acromegaly.

BACKGROUND: Nicotinamide phosphoribosyltransferase (NAMPT)/visfatin is a widely expressed protein with various effects on glucose and lipid metabolism, cell survival, and inflammation. AIM: We hypothesized that NAMPT was related to metabolic disturbances in active acromegaly. METHODS: Body composition, glucose metabolism, and NAMPT levels were measured in 47 patients with active, untreated acromegaly and 24 age-, sex-, and body mass index-matched controls. The in vitro effects of GH/IGF-I on NAMPT expression in human sc adipocytes (SCA), visceral adipocytes, osteoblasts, and hepatocytes were studied. The effects of overnight incubation with the highly specific NAMPT inhibitor FK866 on the GH-stimulated monocyte chemotactic protein-1 and IL-6 expression in mature SCA were evaluated. RESULTS: NAMPT was increased in active acromegaly (P = 0.004) and correlated negatively with limb (arms + legs) fat percentage (% fat, r = -0.32; P = 0.032). After adjusting for age, gender, leptin, and GH, the circulating NAMPT correlated negatively with limb and total body fat percentage (% fat limbs, r = -0.43, P = 0.006; % fat total body, r = -0.36, P = 0.022) and correlated positively with limb and total body lean percentage (% lean limbs, r = 0.31, P = 0.047; % lean total body, r = 0.33, P = 0.034). No correlation between NAMPT and glucose metabolic parameters was found. In vitro studies revealed that GH increased NAMPT expression in adipocytes. The inhibition of NAMPT enzymatic activity attenuated GH-induced monocyte chemotactic protein-1 expression in SCA. CONCLUSIONS: NAMPT is increased in active acromegaly and may be an inflammatory mediator that causes monocyte infiltration in adipose tissue.

Angiotensin converting enzyme I/D, angiotensinogen M235T and AT1-R A/C1166 gene polymorphisms in patients with acromegaly.

Acromegaly is associated with increased morbidity and mortality related to cardiovascular disease. Hypertension is one of the most common cardiovascular risk factors in acromegalic patients. The aim of this study was to investigate association between the frequencies of angiotensin converting enzyme (ACE) I/D, angiotensinogen (AGT) M235T and the angiotensin II type 1 receptor (AT1-R) A/C1166 gene polymorphisms and some clinical parameters of acromegalic patients. Total of 33 acromegalic patients and 63 controls were enrolled to study. We determined the ACE I/D, AGT M235T and AT1-R A/C1166 gene polymorphisms. Serum insulin, glucose, triglyceride, HDL-cholesterol, LDL-cholesterol, growth hormone and Insulin-like growth factor I (IGF-I) levels of subjects were analyzed. The frequencies of ACE and M235T AGT genotype were not significantly different between control and patients. The distribution of AT1R A/C1166 genotypes was significantly different between patients and control subjects (P=0.016). None of the three ACE genotypes, DD, ID and II displayed significant difference in acromegalic patients. A significant difference in systolic blood pressure and the serum IGF-I levels among the three AGT genotype, MM, MT and TT genotypes was found in patient group. Individuals with MT genotypes had significantly higher serum IGF-I levels and systolic blood pressure than MM and TT genotype subjects, P<0.05. In addition, serum triglyceride and HDL levels differed significantly between MM and MT genotypes, P<0.05. However, systolic blood pressure of patients with CC genotypes was found to be significantly higher than AA genotypes individuals in acromegaly group, P<0.05. It can be said that the angiotensinogen MT and AT1R CC1166 genotype carriers may have more risk than other genotypes in the development of hypertension in acromegaly.

Somatostatin analog and pegvisomant combination therapy for acromegaly.

Optimal biochemical control cannot be attained by long-acting somatostatin analog monotherapy in a large proportion of patients with acromegaly. Such therapy might result in increased mortality, poor control of signs and symptoms of disease and decreased quality of life. Combination treatment with somatostatin analogs and pegvisomant (a growth-hormone-receptor antagonist) is, however, highly effective at normalizing the level of insulin-like growth factor I in over 90% of patients and might also have a favorable effect on quality of life in those with biochemically controlled acromegaly. Moreover, whereas pegvisomant monotherapy does not lead to a decrease in the size of the pituitary tumor, combination therapy with somatostatin analogs results in a clinically relevant decrease in tumor size in about 20% of patients. The main adverse effects of combination treatment are transient elevations in the levels of transaminases, which occur in about 15% of patients, especially in those with diabetes mellitus. In this Review, we discuss the available data on the long-term efficacy and safety of somatostatin analog-pegvisomant combination treatment and its potential use in patients with acromegaly.

Analysis of genetic variants of phosphodiesterase 11A in acromegalic patients.

OBJECTIVES: Aberrant cAMP signaling is involved in the pathogenesis of somatotropinomas. The aim of the study was to screen acromegalic patients for the presence of variants of phosphodiesterase type 11A (PDE11A) gene, which have been recently identified in adrenocortical and testicular tumors. SUBJECTS AND METHODS: We sequenced the PDE11A gene-coding region in 78 acromegalic patients and 110 controls. Immunohistochemistry for PDE11A was performed in a subgroup of adenomas and normal pituitary samples. RESULTS: We found 15 nonsynonymous germline substitutions in 13 acromegalic patients (17%), i.e. 14 missense variants (Y727C in six, R804H in one, R867G in four, and M878V in three) and one truncating mutation (FS41X), with a prevalence only slightly higher than that observed in controls (14%). Immunohistochemistry revealed PDE11A expression higher in somatotropinomas than in normal somatotrophs, without significant difference between tumors with or without PDE11A variants, with the exception of two tumors (one with loss of heterozygosity (LOH) at the PDE11A locus and one with FS41X mutation) showing markedly reduced PDE11A staining. No significant differences in hormonal and clinical parameters between patients with or without PDE11A variants were observed, although patients with PDE11A changes showed a tendency to have a more aggressive tumor compared with patients with wild-type sequence (extrasellar extension in 69 vs 45%). CONCLUSIONS: This study first demonstrated the presence of PDE11A variants in a subset of acromegalic patients, which was only slightly more frequent than in controls. The normal expression of the enzyme in the majority of tumor tissues together with the lack of significant clinical phenotype suggests that these variants might only marginally contribute to the development of somatotropinomas.

11beta-hydroxysteroid dehydrogenase activity in acromegalic patients with normal or impaired carbohydrate metabolism.

The 11beta-hydroxysteroid dehydrogenase isoenzymes (11beta-HSD) catalyse the interconversion of cortisol (F) and cortisone (E). Earlier studies demonstrated that growth hormone (GH) and insulin resistance may exert opposite effects on the conversion of E to F by 11beta-HSD type 1. Therefore, in the present study we determined F and E concentrations in 562 plasma samples obtained from acromegalic patients during an active phase (76 patients) and after cure of the disease (68 patients). In addition, we examined whether type 2 diabetes mellitus or impaired glucose tolerance, which are frequently associated with active acromegaly could influence plasma F and E levels in these patients. We found that plasma F concentrations were similar in patients with active acromegaly and in those who were cured with pituitary surgery, irradiation and/or medical therapy (mean+/-S.E., 12.4+/-0.3 and 12.7+/-0.4 microg/dl, respectively). However, plasma E levels were significantly higher in patients with active compared to those with cured acromegaly (2.8+/-0.1 and 2.2+/-0.1 microg/dl, respectively; p<0.001), resulting in a lower F/E ratio in patients with active disease (4.6+/-0.1 vs. 5.9+/-0.2 in the cured group of patients; p<0.001). When the effect of altered carbohydrate homeostasis on plasma F and E was analysed, the results indicated significantly lower plasma E levels and higher F/E ratios in active acromegalic patients with type 2 diabetes mellitus or impaired glucose tolerance compared to those with normal carbohydrate metabolism (E, 2.5+/-0.1 and 3.0+/-0.1 microg/dl, respectively; F/E, 5.1+/-0.2 and 4.4+/-0.1; p<0.001), whereas plasma F concentrations were similar in these two groups (12.1+/-0.4 and 12.6+/-0.3 microg/dl, respectively). These findings indicate that disease activity exerts a significant impact on 11beta-HSD in acromegalic patients, which is further modified with altered carbohydrate homeostasis, frequently present in patients with active disease.

Elevated transaminases during medical treatment of acromegaly: a review of the German pegvisomant surveillance experience and a report of a patient with histologically proven chronic mild active hepatitis.

OBJECTIVE: The new GH receptor antagonist pegvisomant is the most effective medical therapy to normalize IGF-I levels in patients with acromegaly. Based on currently available data pegvisomant is well tolerated; however, treatment-induced elevation of transaminases has been reported and led to the necessity for drug discontinuation in some patients in the pivotal studies. The aim of this study was to evaluate and characterize the prevalence of elevated transaminases and to describe in detail the findings in a single case who required drug discontinuation because of elevation of transaminases which emerged during treatment and who underwent liver biopsy. DESIGN AND METHODS: Retrospective safety analyses were carried out on 142 patients with acromegaly receiving pegvisomant treatment in Germany between March 2003 and the end of 2004. Of these patients, 123 were documented in a post-marketing surveillance study, one case of elevated transaminases was reported spontaneously and the other patients were treated in a clinical study. RESULTS: Mean treatment duration with pegvisomant in the ongoing observational study at the end of 2004 was 28.3 +/- 19.9 (S.D.) weeks. Twelve out of the 142 patients had elevated transaminases above three times the upper limit of normal, likely caused by biliary obstruction in five of the patients. All patients but one affected by elevated transaminases had been previously treated with somatostatin analogues. In six out of 142 (4%) of patients, pegvisomant was permanently withdrawn because of elevated transaminases. The same number of patients showed a transient increase of transaminases with either spontaneous remission without dose modification (n = 4) or no re-increase of transaminases after temporary discontinuation and re-exposure (n = 2). The liver biopsy of one patient who was permanently withdrawn showed a chronic mild hepatitis with a mixed portal inflammation including eosinophilic granulocytes. CONCLUSIONS: Liver function tests should be regularly followed on pegvisomant treatment. Biliary complications, which may arise from restitution of normal gall bladder motility after cessation of somatostatin analogue treatment, need to be differentiated from pegvisomant-induced abnormalities. The histological pattern of the liver biopsy performed in one of the patients showed a mild chronic active hepatitis. The lack of dose dependency and rather low frequency of elevated transaminases in those cases where a biliary disorder was excluded render this reaction an idiosyncratic drug toxicity.

Effects of angiotensin-converting enzyme gene polymorphism on the left-ventricular function and mass in patients with acromegaly.

In this study we have investigated the contribution of the ACE genotype to the development of left-ventricular hypertrophy (LVH) and systolic and diastolic dysfunctions in acromegalic patients. The study group consisted of 30 acromegalic patients (21 women and 9 men, age: 37.9 +/- 10.8 years, disease duration: 9.0 +/- 6.9 years). The distribution of the DD, ID and II genotypes was 40.0 (n = 12), 46.6 (n = 14) and 13.3% (n = 4), respectively, being similar to frequencies observed in a healthy population. Plasma ACE levels were 55.0 +/- 12.0 (45-84), 28.7 +/- 15.7 (8-58) and 24.5 +/- 12.0 (16-33) U/I in patients with the DD, ID and II genotype, respectively. The mean serum ACE activity in the DD genotype was significantly higher than in the heterozygous group (p < 0.0001). Serum ACE activity showed a significant negative association with the mean growth hormone level (r = -0.52, p = 0.007). The LV early diastolic flow velocity/LV presystolic flow velocity (E/A) ratios were 1.2 +/- 0.4 for the DD genotype, 1.3 +/- 0.3 for the ID genotype and 0.7 +/- 0.1 for the II genotype. The E/A ratio was considerably lower in acromegalic patients with the II genotype compared to the other genotypes (p = 0.03). The LV mass index (LVMI) values were 131.5 +/- 4.2 g/m2 for the DD genotype, 141.7 +/- 50.3 g/m2 for the ID genotype and 159.6 +/- 48.2 g/m2 for the II genotype. However, there was no significant difference in LVMI among allelic groups. All other indices of systolic and diastolic function were not statistically different in the acromegalic patients. The present data fail to support a role of ACE gene polymorphism in determining LVH in acromegalic patients. However, the I allele may prove as a useful marker predicting the development of diastolic dysfunction in acromegalic patients.

Impaired activation of phosphoinositide 3-kinase by insulin in fibroblasts from patients with severe insulin resistance and pseudoacromegaly. A disorder characterized by selective postreceptor insulin resistance.

Some patients with severe insulin resistance develop pathological tissue growth reminiscent of acromegaly. Previous studies of such patients have suggested the presence of a selective postreceptor defect of insulin signaling, resulting in the impairment of metabolic but preservation of mitogenic signaling. As the activation of phosphoinositide 3-kinase (PI 3-kinase) is considered essential for insulin's metabolic signaling, we have examined insulin-stimulated PI 3-kinase activity in anti-insulin receptor substrate (IRS)-1 immunoprecipitates from cultured dermal fibroblasts obtained from pseudoacromegalic (PA) patients and controls. At a concentration of insulin (1 nM) similar to that seen in vivo in PA patients, the activation of IRS-1-associated PI 3-kinase was reduced markedly in fibroblasts from the PA patients (32+/-7% of the activity of normal controls, P < 0.01). Genetic and biochemical studies indicated that this impairment was not secondary to a defect in the structure, expression, or activation of the insulin receptor, IRS-1, or p85alpha. Insulin stimulation of mitogenesis in PA fibroblasts, as determined by thymidine incorporation, was indistinguishable from controls, as was mitogen-activated protein kinase phosphorylation, confirming the integrity of insulin's mitogenic signaling pathways in this condition. These findings support the existence of an intrinsic defect of postreceptor insulin signaling in the PA subtype of insulin resistance, which involves impairment of the activation of PI 3-kinase. The PA tissue growth seen in such patients is likely to result from severe in vivo hyperinsulinemia activating intact mitogenic signaling pathways emanating from the insulin receptor.

Clinical and biochemical characteristics of acromegalic patients harboring gsp-positive and gsp-negative pituitary tumors.

A subgroup of growth hormone (GH)-secreting pituitary tumors carries somatic mutations within the gene coding for the alpha subunit of the stimulatory heterotrimeric guanosine 5'-triphosphate-binding protein, Gs alpha. These so-called gsp mutations result in constitutively activated Gs alpha and the signal transduction cascade downstream of it, with eventual markedly and continuously elevated cyclic adenosine monophosphate levels as a result of constitutive adenylyl cyclase activity. It is this elevation of intracellular cyclic adenosine monophosphate that is thought to be the cause of excessive GH secretion and somatotroph proliferation. We examined the clinical and biochemical characteristics of acromegalics harboring gsp-positive and gsp-negative pituitary tumors. Of 19 tumors studied, 8 (42%) were gsp positive. There was a slight tendency for basal GH levels in serum to be lower and to be further reduced by an oral glucose tolerance test in gsp-positive patients. However, there was no difference between the two groups in terms of clinical features, tumor size, mitotic activity (as assessed by cytosolic deoxyribonucleic acid polymerase and KI-67 staining), and in vitro GH response to GH releasing factor. We conclude that there is, in general, little difference in the clinical and biochemical characteristics between gsp-positive and gsp-negative human pituitary GH-secreting tumors.

Immunohistochemical expression of protein kinase C type III in human pituitary adenomas.

Immunohistochemical expression of the three major isozymes of protein kinase C--Types I, II, and III--was studied in 32 cases of human pituitary adenomas, and the results were compared in detail with their clinical data. Immunoreactivity for the Type I and Type II isozymes was negative in tumor cells of all pituitary adenomas. Moderate to strong cytoplasmic immunoreactivity for the Type III isozyme was constantly seen in acromegaly, Cushing's disease, and nonfunctioning adenomas, which indicated overexpression of the isozyme, since only slight cytoplasmic immunoreactivity was observed in the normal human anterior pituitary cells. Among 13 prolactinomas, 5 cases showed positive immunoreactivity for Type III in all tumor cells, whereas 8 cases showed negative immunoreactivity for the isozyme in all or more than 85% of tumor cells. The sizes of the tumors in this protein kinase C Type III negative group of prolactinomas tended to be smaller than those of the Type III positive prolactinomas. Also, the negative immunoreactivity for Type III was predominantly observed in those cases where prolactinomas were relatively well controlled by continuous oral dosage of dopamine agonists before operation. These results suggest that protein kinase C Type III is closely involved in human pituitary adenomas. The exceptional negativity for the isozyme in prolactinomas may be relevant to the suppression of tumor growth by dopamine agonists.

N-acetyl-beta-glucosaminidase and albuminuria in acromegaly.

Significantly increased albuminuria and N-acetyl-beta-glucosaminidase activity in serum and urine have been observed in acromegalic patients in comparison with healthy persons (P less than 0.001). No relationship between these biochemical variables and serum growth hormone or insulin concentration was found in our group of patients. Significant correlation was determined between urinary NAG activity and albuminuria of acromegalic patients (r = 0.84).

Clinical, biochemical, and morphological correlates in patients bearing growth hormone-secreting pituitary tumors with or without constitutively active adenylyl cyclase.

Somatic mutations in the alpha-chain (alpha s) of the stimulatory regulatory protein of adenylyl cyclase (Gs) causing constitutive activation of the enzyme have been identified in a subset of human GH-secreting pituitary adenomas. This study reports on the differences between acromegalic patients bearing tumors without (group 1; n = 51) or with (group 2; n = 29) this alteration. No difference in age, sex, clinical features, duration of the disease, or cure rate was observed between the two groups. By contrast, group 2 patients had higher basal GH levels than group 1. Moreover, a significant difference in sellar morphology was found; group 2 patients more frequently showed sellas of normal size (grade I) than group 1. Hypersecretory activity of group 2 tumors was also apparent at electron microscopy; contrary to those of group 1, cells of group 2 tumors were densely granulated and showed prominent rough endoplasmic reticulum and Golgi complex. With respect to group 1, group 2 patients were less responsive to GH-releasing hormone, while they were more sensitive to somatostatin- and dopamine-induced GH inhibition. These results suggest that patients with constitutively active adenylyl cyclase have hyperactive tumors; the sensitivity of these tumors to inhibitory agents (somatostatin and dopamine), possibly counteracting the expression of activating mutations, might explain the low rate of tumor growth.

Thyroxine 5'-deiodinase in human anterior pituitary tumors.

The activity of T4 5'-monodeiodinase (5'D) in the pituitary was measured in 12 patients with pituitary adenoma (3 patients with acromegaly, 2 with prolactinoma, 1 with Cushing's disease, 1 with TSH-producing tumor, and 5 with nonfunctioning tumor) and, as a control, in a patient who died of parotid cancer. The pituitaries, obtained at operation or autopsy, were homogenized in 0.1 mol/L potassium phosphate buffer, pH 7.0, and centrifuged at 800 x g. Supernatants were incubated with [125I]T4 and 20 mmol/L dithiothreitol (DTT) at 37C for 90 min. T4 5'-D was measured by the release of 125I- with the ion exchange method. The activity of T4 5'-D in the pituitaries from patients with prolactinoma and parotid cancer was dependent on protein concentration, incubation time, incubation temperature, and T4 concentration, and was labile to prior heating at 70 C for 30 min. T4 5'-D was not inhibited by 1 mmol/L propylthiouracil, but was inhibited 95% by 0.1 mmol/L iopanoic acid. The apparent Km and maximum velocity for T4 5'-D in homogenates of prolactinoma at 20 mmol/L DTT were 11 nmol/L and 1.54 pmol/mg protein.h, respectively. This reaction followed sequential-type reaction kinetics when the DTT concentration was varied. All other homogenates of pituitary tumors, except two nonfunctioning tumors, also demonstrated T4 5'-D activity. These results indicate that 1) the human pituitary express a low Km and PTU-insensitive T4 5'-D activity which is very similar to the type II enzyme activity in the rat pituitary; and 2) various types of pituitary tumor cells contain T4 5'-D activity.

[Bone alkaline phosphatase as an activity parameter of acromegaly]. / Alkalische Knochenphosphatase als Aktivitätsparameter der Akromegalie.

Serum levels of growth hormone (GH: arithmetic mean of three measurements eight hours apart), somatomedin C (SmC), alkaline phosphatase activity and the bone isoenzyme of alkaline phosphatase (as the liver/bone isoenzyme ratio) were measured in 26 patients with acromegaly (11 men and 15 women; mean age 45.5 [24-66] years), 18 in the active and eight in the nonactive phase of the disease. Activity was characterized by a raised (660 [330-1149] ng/ml), inactivity by a normal (186 [40-300] ng/ml) SmC concentration. All 18 patients with active acromegaly had an abnormally low liver/bone isoenzyme ratio (mean of 0.66 [0.01-1.28]). In seven of the eight patients with inactive acromegaly it was within normal limits. Thus measurement of bone alkaline phosphatase, which is significantly cheaper than that of SmC, is suitable for assessing activity.

High activity of cyclic 3',5'-nucleotide phosphodiesterase in sera of patient with phaeochromocytoma.

Our previous observations that serum cyclic 3',5'-nucleotide phosphodiesterase activity varied in thyroid disorders and was positively correlated with thyroid function stimulated us to investigate the phosphodiesterase levels in sera of patients with pituitary and adrenal disorders, and the response to glucagon in normal subjects. Both serum cyclic AMP phosphodiesterase (cyclic AMP-PDE) and cyclic GMP phosphodiesterase (cyclic GMP-PDE) activities were measured at a low substrate concentration. Serum cyclic AMP-PDE activity was elevated in five patients with phaeochromocytoma and was not elevated in patients with Cushing's syndrome or acromegaly, compared to the level in normal subjects. Increased enzyme activities returned to normal after resection of the tumours. Intramuscular injection of glucagon to five healthy subjects elevated cyclic AMP levels and cyclic AMP-PDE activity in plasma. These results imply that the increased cyclic AMP level by the activation of cyclase may have induced cyclic AMP-PDE in the target organ and the soluble cyclic AMP-PDE may leak into blood vessels from target organs.

Human nasal septal cartilage: local distribution of different enzyme activities in healthy adults and acromegalic patients.

Septal cartilage was obtained during septoplasty from healthy adults or during transnasal hypophysectomy from acromegalic patients. Small strips of cartilage were excised from five different areas of the septum: the anterior free end, the suprapremaxillary area, the central area, the posterior area, and the caudal prolongation of the septum. Five different enzymatic pathways were analyzed in these areas. Cathepsin D, an acid proteinase, did not show a specific local activity pattern and was not influenced by the augmented growth hormone level in acromegaly, whereas cathepsin B, a neutral proteinase, showed its highest activity in the caudal prolongation and the posterior area and was significantly increased in all areas in acromegaly. Beta-hexosaminidase activity was highest in the central and posterior area and caudal prolongation of the septum. In acromegaly, a significant increase of its activity was found in the suprapremaxillary and posterior area. Acid phosphatase activity was highest in the caudal prolongation of the septum, but its activity was significantly increased in all tested areas in acromegaly. Alkaline phosphatase activity could only be found in the posterior area and the caudal prolongation in healthy adults. However, in acromegaly this enzyme could be detected in the central area and the posterior end of the suprapremaxillary area suggesting an altered process of mineralization. A distinct local pattern of enzymes related to intercellular substance metabolism and mineralization can be demonstrated in the septal cartilage of healthy adults and acromegalic patients.

Neuron-specific enolase in the pituitary gland.

Neuron-specific enolase (NSE) is present in many types of peptide-secreting neuroendocrine cells and in tumours derived from them, but little work has been done on the pituitary gland. Serial sections of normal rat (n = 9) and human (n = 7) pituitary gland, spontaneous rat pituitary tumours (n = 14) and human pituitary tumours, both hormonally active (n = 7) and inactive (n = 10), were immunostained for NSE and the 6 major anterior pituitary hormones. The neural lobe stained strongly and the intermediate lobe variably for NSE. In the anterior lobe, NSE immunoreactivity was present with variable intensity in the majority of hormone-producing cells of all six types. Cells with strong hormone immunoreactivity were usually only moderately stained for NSE. All the human and rat pituitary adenomas examined were positively stained for NSE, though to varying degrees. The pituitary gland is thus no exception to the rule that NSE is found in peptide-secreting neuroendocrine cells and their tumours.

Decline of postheparin plasma lipoprotein lipase in acromegalic patients.

Lipoprotein lipase and hepatic triglyceride lipase in postheparin plasma were measured in seven patients with active acromegaly by an immunochemical method utilizing antiserum prepared against hepatic triglyceride lipase. A mild or moderate hypertriglyceridemia was shown, with plasma triglyceride concentrations between 156 and 544 mg/dl. Lipoprotein lipase was found to be decreased in all patients (p less than 0.001). Hepatic triglyceride lipase was also low in these patients (p less than 0.001). We speculate that acromegalic hypertriglyceridemia is mediated, at least in part, by the decline in lipoprotein lipase and possibly by the decline in hepatic triglyceride lipase activities.

Bone isoenzyme of serum alkaline phosphatase in acromegaly.

In 37 patients with active acromegaly and in 15 patients with inactive acromegaly, activity of bone isoenzyme of serum alkaline phosphatase correlated (P less than 0.001) with serum concentration of immunoreactive growth hormone. By using stepwise regression analysis, the predication of serum growth hormone values based on serum levels of bone isoenzyme of serum alkaline phosphatase, gamma-glutamyl transferase and calcium in these patients with acromegaly was within 1 S.D. range in 37 patients and in only 2 patients was it out of 2 S.D. range. By using discriminant analysis, based on bone and liver isoenzymes of serum alaline phosphatase and urinary hydroxyproline excretion, 87%, 60% and 97% of the classification of patients with active and inactive acromegaly and healthy adults, respectively, was correct. The multivariate approach offers a quantitative appraisal of the biochemical parameters of peripheral growth hormone action used as an indicator of growth hormone concentration in patients with acromegaly.

Relationship of the activity of the bone isoenzyme of serum alkaline phosphatase to urinary hydroxyproline excretion in metabolic and neoplastic bone diseases.

A significant correlation between the activity of the bone isoenzyme or serum alkaline phosphatase and the urinary hydroxyproline excretion in osteomalacia, osteoporosis, primary hyperparathyroidism with osteodystrophy, Paget's disease, secondary bone tumours, and in a control group was found (P less than 0.001). This close correlation was not observed between these variables in patients with active acromegaly. Diagnosis determined from these indices of formation and turnover of bone matrix agreed with that established by histological and histochemical examination of bone, by X-ray investigation of the skeleton, and by the radionuclear 85Sr test. The relationship between the activity of bone isoenzyme and urinary hydroxyproline excretion differed in metabolic bone diseases with a high bone turnover, in patients with osteoporosis and in patients with early osteoclastic bone metastases.