[Hyponatremia: Differential Diagnosis and Treatment]. / Hyponatriämie: Differenzialdiagnose und Therapie.

Hyponatremia is the most common electrolyte abnormality seen in hospitalized patients, with up to 30 % having a plasma sodium concentration below 135 mmol/l. It is now clear that the clinical problem extends beyond the neurological symptoms, which can be explained by intracerebral osmotic fluid shifts and brain edema. Instead, chronic hyponatremia is associated with impaired gait stability and an increased risk of bone fragility fractures. Moreover, hyponatremia has been demonstrated to be an indicator of poor prognosis in a variety of conditions.Hyponatremia can be a life-threatening disorder due to increased intracranial pressure, thus requiring prompt and efficacious treatment. However, overly rapid correction may be complicated by osmotic demyelination syndrome with catastrophic clinical sequelae, i. e., spastic quadriparesis, or even coma or death.To avoid inappropriate treatment, the underlying pathophysiology in each case as well as the time course (acute vs. chronic) and the clinical and biochemical severity must be considered.The purpose of this review is to provide the reader with a systematic approach to the correct diagnosis and management of hyponatremia based on available European and international guidelines.

Prevalence and Predictors of Overweight and Obesity in Patients with Pituitary Dysfunctions.

BACKGROUND: Patients with hypothalamic-pituitary disorders (HPD) may be of increased risk to develop overweight and obesity, thereby fostering cardiovascular events. However, it remains unclear if patients with pituitary dysfunctions per se have an increased risk of becoming obese. OBJECTIVE: The objective of this study was to evaluate prevalence and to identify possible predictors of overweight and obesity in patients with pituitary dysfunctions. METHODS: A total of 121 out-patients having various causes for HPD were assessed for height and body weight; body mass index (BMI) was calculated and correlated with clinical features. Patients were divided into various subgroups depending on underlying conditions and therapeutic modalities. RESULTS: Most of the HPD patients were overweight or obese with males being significantly more affected. Of interest, patients with macroadenomas suffered significantly more often from overweight and obesity than individuals with microadenomas (73.4% vs. 43.5%, p= 0.006). Increased BMI (≥25 kg/m2) tended to be more common in patients with prolactinomas (70.0%), hormone deficiencies (76.1%) and hormone replacement therapies (76.6%) than in a healthy population. CONCLUSION: In conclusion, we showed that patients with HPD: (i) frequently suffer from overweight and obesity; (ii) prevalence of overweight and obesity however is comparable to that in the general population; (iii) only patients with macroadenomas seem to have a significantly higher risk; (iv) hormone deficiencies and hormonal replacement therapy may foster weight gain and (v) radiation and surgical tumour therapy per se do not seem to be additional risk factors for weight gain.

Exploring the Impact of Short- and Long-Term Hydrocortisone Replacement on Cognitive Function, Quality of Life and Catecholamine Secretion: A Pilot Study.

Hydrocortisone (HC) substitution is essential in the treatment for patients with adrenal insufficiency (AI). Current replacement regimens however only incompletely mimic the physiological circadian rhythm of cortisol secretion, thereby resulting in subclinical temporary hypo- and hypercortisolism. Several studies point toward impairment of cognitive functions under these conditions, in part due to affected catecholamine secretion. Aim of this study was to evaluate the influence of long-term versus short-term HC replacement therapy on the adrenomedullary system and cognitive functions. Fourteen patients with primary or secondary AI were divided into two groups, depending on the duration of disease and HC replacement therapy (<15 years). All subjects underwent standardized neurocognitive testing; in addition, cortisol and catecholamine levels as well as physiological parameters and quality of life (QoL) were assessed. Patients with HC replacement therapy ≥15 years (n = 7) received significantly higher equivalent glucocorticoid doses than those with a shorter lasting therapy (n = 7; p = 0.048). Neuropsychological tests, QoL, physiological parameters, and cortisol levels did not differ significantly between both groups. Of note, norepinephrine levels were significantly lower in patients on short-term HC replacement therapy (p = 0.025). However, there were no significant differences in catecholamines with respect to the underlying pathophysiology, gender, or age. Irrespective of the duration of use, male patients scored significantly better for single aspects of QoL, whereas females performed significantly better in the attention test. Overall, we showed that duration of cortisol replacement therapy may have an impact on catecholamine release, but does not seem to affect cognitive functions and QoL.

High prevalence of fibromyalgia-associated symptoms in patients with hypothalamic-pituitary disorders.

OBJECTIVES: Various complaints of patients with fibromyalgia often resemble clinical features observed in patients with hypothalamic-pituitary diseases. The aim of this study was to evaluate whether patients with hypothalamic-pituitary diseases are at increased risk for fibromyalgia syndrome (FMS). METHODS: A questionnaire for evaluating fibromyalgia-associated symptoms was sent to 121 patients with hypothalamic-pituitary disorders (HPD) (60 women, 61 men; mean age, 55.4 years; range, 21-83 years) of the endocrine outpatient clinic. 115 patients (57 women, 58 men; mean age 56.9 years; range, 21 to 82 years) with cardiovascular diseases (CD) served as controls. RESULTS: Fibromyalgia-associated symptoms regarding muscular complaints were significantly more frequent in the HPD group than in CD patients (53.7 % vs. 35.7%, p= 0.003). In particular, we found a significant higher prevalence of autonomic symptoms in the HPD group as compared to the CD group regarding several qualities (cold hands, p=0.039; flatulence, p=0.022; tiredness, p=0.017). In addition, swollen and painful finger joints were reported more often in the HPD group than in the CD group (p=0.002). Of note, no differences regarding any fibromyalgia-associated symptom were detected when patients with hypothalamic-pituitary hormone excess syndromes were compared to those with a pituitary pathology without hormonal excess. Similarly, prevalence of fibromyalgia-associated symptoms was not related to the treatment modality of pituitary disease; i.e. surgical vs. conservative or any hormonal replacement therapy. CONCLUSIONS: Our data suggest that patients with hypothalamic-pituitary disorders may be at increased risk of developing fibromyalgia-associated symptoms.

Can peripheral blood γδ T cells predict osteonecrosis of the jaw? An immunological perspective on the adverse drug effects of aminobisphosphonate therapy.

Nitrogen-bisphosphonates (n-BP), often referred to as aminobisphosphonates, are the most commonly prescribed drugs for the treatment of disorders of bone fragility. However, long-term continuous treatment predisposes certain individuals to serious rare side effects, such as bisphosphonate-associated osteonecrosis of the jaw (BAONJ). n-BP use is known to unintentionally activate a subset of innate T cells called Vγ9Vδ2 T cells, but the consequence of this chronic immune stimulation has remained unexplored. The primary objectives of this study were to 1) determine the fate of Vγ9Vδ2 T cells in osteoporotic patients on n-BP therapy as a function of time and type of therapy; 2) evaluate the proportion of Vγ9Vδ2 T cells in patients who had recently experienced n-BP-associated ONJ. We found there is a notable loss of Vγ9Vδ2 T cells over time in osteoporotic patients on n-BP therapy, particularly those on intravenous (iv) therapy (Spearman r = -0.55, p < 0.0001 iv; r = -0.3, p < 0.03 oral) (n = 68); no difference was observed in total T cells, monocytes, or granulocytes. Importantly, the observed negative effect on Vγ9Vδ2 T cells coincides with the reported route of administration and timing of the rare occurrence of BAONJ. Patients (n = 6) who had experienced BAONJ were all found to be significantly deficient in Vγ9Vδ2 T cells (median = 0.07%) in comparison to age- and sex-matched treatment-naïve controls (N = 11; median = 2.40%), U = 0, p = 0.001; this was the only consistent difference in the leukocytes assessed. All BAONJ cases had an underlying condition that further contributed to impaired immunity. We propose Vγ9Vδ2 T cells show a strong potential to serve as harbingers of possible adverse immune effects of n-BP therapy, particularly in those patients already having a compromised immune system as they may be most vulnerable to the development of conditions such as BAONJ.

Effects of short-term nocturnal cortisol replacement on cognitive function and quality of life in patients with primary or secondary adrenal insufficiency: a pilot study.

Cortisol replacement in patients with adrenal insufficiency usually consists of hydrocortisone (HC) given orally during day time. Due to the short half-life of hydrocortisone, cortisol levels between midnight and early morning are very low in contrast to the physiological rise of cortisol serum levels during this time. We investigated whether short-term cortisol replacement during the night improves cognitive function and well-being in these patients. Fourteen patients with adrenal insufficiency were put on HC infusion between midnight and 8 a.m. They subsequently underwent neurocognitive testing to measure intellectual functioning, concentration, memory and fine motor skills. Quality of life and mood were also evaluated. All tests were repeated after 2-4 weeks during usual oral glucocorticoid replacement therapy. Blood samples were taken for cortisol, epinephrine and norepinephrine measurement. With the exception of the digit symbol test with better scoring in the oral group (p = 0.005) there were no significant differences in neurocognitive testing, vegetative functions and quality of life on the two occasions. However, a higher cortisol level was associated with a worse performance in short-term memory. Plasma epinephrine concentration was subnormal in both groups, but increased only after intravenous hydrocortisone replacement. Mimicking the physiological rise in cortisol secretion during the night in this pilot study did neither significantly affect quality of life nor cognitive performance and vegetative functions. There was no improvement in general well being. Hydrocortisone infusion during night time might improve adrenomedullary reserve in patients with adrenal insufficiency.

Tumor-induced osteomalacia: successful treatment by radio-guided tumor surgery.

Tumor-induced osteomalacia is a rare syndrome characterized by urinary phosphate loss with hypophosphatemic osteomalacia. The proposed pathogenetic mechanism is paraneoplastic secretion of phosphaturic factors (so-called phosphatonins).We describe a 34-year-old male patient who presented with severe pain of the spine and ribs for at least 2 years. Bone scintigraphy using Technetium hydroxymethylene diphosphonate (Tc HDP) showed multiple lesions suggesting metastatic disease. Bone biopsy however revealed osteomalacia. The patient had subnormal plasma phosphate levels (0.42 mmol/L; normal range, 0.87-1.45) and markedly increased phosphate clearance (82.8 mL/min; normal range, 5.4-16.2). The patient was treated with phosphate supplementation (up to 5 g daily) along with calcium (1000 mg daily) and calcitriol (1.5 microg daily). Although this therapy did not correct hypophosphatemia, it resulted in complete relief of pain within several months. (111)In pentetreotide scintigraphy showed a tiny lesion of 1-cm diameter, which could be localized to the left femoral neck in close vicinity to the greater trochanter by MRI and image fusion analysis. This lesion had not been visualized by Tc-99m HDP bone scintigraphy. Intraoperatively, use of a hand-held gamma probe after administration of (111)Indium pentetreotide ((111)In pentetreotide) clearly identified the tumor, which was completely removed and was shown to be a hemangiopericytoma. After removal of the tumor, phosphate metabolism normalized within 1 week without requirement of phosphate supplementation. Hypophosphatemic osteomalacia, although rare, raises an important differential diagnosis. An underlying tumor may be detected only by (111)In pentetreotide scintigraphy. Preoperative labeling with (111)In pentetreotide is a useful tool in detecting these tumors during surgery.This 34 year old man with osteomalacia had a small causative hemangiopericytoma detected in the indium pentetreotide scintography.

Familial influences and obesity-associated metabolic risk factors contribute to the variation in resting energy expenditure: the Kiel Obesity Prevention Study.

BACKGROUND: A low metabolic rate may be inherited and predispose to obesity, whereas a higher metabolic rate in obesity may be acquired by obesity-associated cardiometabolic risk. OBJECTIVE: We aimed to explain the interindividual variation in resting energy expenditure (REE) by assessing 1) the association between REE and body composition, thyroid hormones, and obesity-related cardiometabolic risk factors, and 2) the familial (genetic and environmental) contribution to REE. DESIGN: REE and metabolic risk factors (ie, blood pressure and plasma insulin, glucose, and C-reactive protein concentrations) were assessed in 149 two- or three-generation families, including at least one overweight or obese member. Heritability of REE, respiratory quotient (RQ), thyroid hormones [thyrotropin (TSH), free triiodothyronine (FT3) and free thyroxine (FT4)], and body composition (fat-free mass and fat mass) were estimated by using variance components-based quantitative genetic models. RESULTS: REE adjusted for body composition, sex, and age (REEadj) significantly correlated with systolic and diastolic blood pressure, plasma insulin and glucose concentrations, and the homeostasis model assessment (HOMA) (r = 0.14-0.31, P < 0.05). Thyroid hormones had a modest influence on REE variance only. Heritability was 0.30 +/- 0.07 for REEadj and 0.29 +/- 0.08 for REE after additional adjustment for thyroid hormones and metabolic risk. Furthermore, heritability was estimated to be 0.22 +/- 0.08 for RQ, 0.37 +/- 0.08 for TSH, 0.68 +/- 0.06 for FT4, and 0.69 +/- 0.05 for FT3 (all significantly larger than zero). CONCLUSIONS: Obesity-related cardiometabolic risk factors contribute to interindividual variation in REE, with hypertension and insulin resistance being associated with a higher REE. REE was moderately heritable, independent of body composition, sex, age, thyroid function, and cardiometabolic risk.

Measurement of waist circumference at four different sites in children, adolescents, and young adults: concordance and correlation with nutritional status as well as cardiometabolic risk factors.

BACKGROUND: This study investigates the concordance of four waist circumference (WC) measurement sites, and examines their relationships with nutritional status and cardiometabolic risk. SUBJECTS AND METHODS: In 91 females / 89 males (6.1-19.9 years; 12.2% overweight), WC was assessed beneath the lowest rib (WCR), 4 cm above the umbilicus (WC4), above the iliac crest (WCC), and midway between WCR/WCC (WCM). 'Overwaist' was defined as a WC > 90th age-/sex-specific percentile. Pubertal stage was assessed according to Tanner. Body composition (air-displacement plethysmography), blood pressure, lipid profile, glucose/insulin levels, and HOMA-IR (homeostasis model assessment of insulin resistance) were measured. RESULTS: Medians of WCs (cm) for females/males were WCR (64.4/69.5) < WC4 (64.6/70.2) < WCM (67.1/71.2) < WCC (71.5/ 74.2). Although closely related to each other (all r > 0.93; p < 0.001), paired comparisons revealed differences between WCs in their magnitudes which was stronger for females than males. Prevalence of 'overwaist' differed according to measurement site in females/males: WCR (13.2/15.7%) < WC4 (14.3/ 19.1%) < WCM (18.7/22.5%) < WCC (37.4/30.3%). After adjusting for age and pubertal status, WCs were closely related to body mass index (BMI) (all r > 0.86; p < 0.001), percent fat mass (%FM; all r > 0.61; p < 0.001), and comparably associated with cardiometabolic risk factors. However, stronger correlations were found for i) WCR vs. WC4 with BMI in males (r = 0.93 vs. 0.91; p < 0.05), ii) WCC vs. WC4 with %FM in females (r = 0.67 vs. 0.61; p < 0.05), iii) WCC vs. WCR with triglycerides in females (r = 0.29 vs. r = 0.22; p < 0.05), and iv) WCC (r = 0.36) vs. other WCs (r = 0.30-0.32) with low-density lipoprotein cholesterol (LDL-C) in males (p < 0.05). CONCLUSION: WCs measured at different sites were closely correlated with BMI and %FM as well as comparably associated with cardiometabolic risk factors. However, different WCs had different magnitudes, which was more obvious in females and led to discordant results with respect to 'overwaist' and risk assessment.

Differential regulated expression of keratinocyte growth factor and its receptor in experimental and human liver fibrosis.

BACKGROUND AND AIM: Immunomodulatory and protective properties have been identified for the keratinocyte growth factor (KGF). For hepatocytes, pro-proliferative and anti-apoptotic effects of this growth factor have been reported in vitro. This study was designed to characterize a putative role of KGF in observed histomorphological changes in both, human and experimental liver fibrosis. METHODS: Liver fibrosis and cirrhosis was induced in rats by repetitive exposure to phenobarbitone and increasing doses of carbon tetrachloride. Human samples were obtained from patients undergoing surgery for partial hepatectomy or transplantation. Organ samples were scored for inflammation and morphological changes. Expression of KGF and its receptor (KGFR) mRNA was quantified by real-time RT-PCR. Protein expression and receptor phosphorylation was determined by Western blot analysis. In-situ hybridization and immunohistochemistry were utilized to determine distribution of KGF and KGFR in the liver. RESULTS: Expression of KGF was significantly increased in damaged liver tissue in correlation to the degree of fibrosis, whereas expression of the receptor was up-regulated in early stages of liver fibrosis and down-regulated in cirrhotic organs. Protein expression of this growth factor and its receptor correlated with the alterations in mRNA. KGF expression was restricted to mesenchymal cells, whereas expression of KGFR was detected on hepatocytes only. CONCLUSION: The expression of KGF and KGFR is differentially and significantly regulated in damaged liver tissue. This growth factor might therefore not only contribute to morphological alterations but also regeneration of liver parenchyma most likely mediated by indirect mechanisms of action.

Androgen receptors and gender-specific distribution of alkaline phosphatase in human thyroid cartilage.

The degree of mineralization in human thyroid cartilage is gender specific. Until now, laryngeal tissue was tested for sexual hormone receptors by the use of radiolabelled hormones only without exact localization of the receptors. In this study immediately frozen cartilage specimens from seven male and one female patient who underwent laryngectomy were used for immunolocalization of sexual hormone receptors. Additionally, serum sexual hormone levels were measured by means of radioimmunoassay. Alkaline phosphatase was localized enzymohistochemically in another cohort of six male and four female cartilage specimens from laryngectomies and autopsies. Chondrocytes in thyroid cartilage from both sexes reacted with antibodies to the androgen receptor. The low serum testosterone levels, which varied between 1.5 and 3.9 ng/ml, did not correlate with insufficient mineralization of thyroid cartilage in men (r=0.363, P=0.432). Chondrocytes did not react with antibodies to the estrogen receptor alpha and the progesterone receptor in both sexes. Expression of alkaline phosphatase started about the middle of the second decade. Some chondrocytes near the mineralization front were positive for androgen receptor and alkaline phosphatase, other chondrocytes were negative for both. Our results suggest the involvement of androgen receptor positive chondrocytes in thyroid cartilage mineralization, probably by a testosterone-linked stimulation of alkaline phosphatase.

Congenital adrenal hyperplasia in adulthood: do men need to continue treatment?

Due to early diagnosis and appropriate paediatric treatment, internists and endocrinologists are now caring for an increasing number of adult patients with congenital adrenal hyperplasia (CAH). Problems that may be encountered in adult males with CAH are the continuing risk of developing an adrenal crisis and impaired gonadal function due to suppression of the hypothalamic-gonadal axis. Fertility may be further compromised by testicular adrenal rest tumours. Available data suggest that the reversal of infertility is more difficult once testicular nodules have developed. Similar to female CAH patients, male patients may develop adrenal tumours due to inadequate adrenocorticotropic hormone suppression. We therefore recommend continuous treatment of male CAH patients with careful monitoring of clinical and hormonal parameters in order to avoid overtreatment.

Persistent hyperinsulinemic hypoglycemia in 15 adults with diffuse nesidioblastosis: diagnostic criteria, incidence, and characterization of beta-cell changes.

Persistent hyperinsulinemic hypoglycemia (PHH) in adults that is not caused by an insulinoma is a rare and not well-characterized disease that has been named nesidioblastosis. In this study, we defined and scrutinized criteria for its histologic diagnosis, assessed its relative incidence, and discussed its pathogenesis. In pancreatic specimens from 15 adult patients with PHH in whom no insulinoma was detected and in 18 adult control patients, the endocrine tissue was screened for islet and beta-cell changes. The diagnostic reliability of the findings was checked by an interobserver analysis. The relative frequency of the disease was assessed in a series of 232 patients with PHH. Finally, genetic analysis of the menin gene was performed. Among the various indicators of islet changes, beta-cell hypertrophy characterized by enlarged and hyperchromatic beta-cell nuclei was the most significant and diagnostic finding in patients with PHH. The interobserver analysis revealed 100% specificity and 87.7% sensitivity. The hyperfunctional state of the beta-cells was not associated with changes in the subcellular distribution of insulin and proinsulin, proliferative activity, or mutations of the menin gene. Our results indicate that diffuse nesidioblastosis in adult patients with PHH resembles that seen in neonates suffering from PHH. The most important criterion for the diagnosis is the beta-cell hypertrophy. As approximately 4% of adult patients with PHH are affected by diffuse nesidioblastosis, this disease is not as rare as it has been thought to be. Pathogenetically, the defective insulin secretion could be based on a molecular defect.

Expression of functional prolactin and its receptor in human colorectal cancer.

BACKGROUND AND AIMS: Ectopic production of prolactin has been reported for several tumors, and elevated prolactin plasma levels have been detected in colorectal cancer patients. However, the role of prolactin in colorectal cancer remains unclear. We therefore compared expression patterns of prolactin and its receptor in normal and neoplastic colonic mucosa of the same patient with noncancer controls and determined mitogenic effects in vitro. MATERIALS AND METHODS: mRNA and protein expression was analyzed by semiquantitative RT-PCR and western blotting. Localization of ligand and receptor in tissues was investigated by immunohistochemistry. Mitogenic effects of prolactin on colorectal cancer cell lines (Caco-2, HT-29, LoVo) were assayed by [(3)H]thymidine incorporation. RESULTS: mRNA expression of prolactin was detected in 13% of normal and 27% of cancer specimens, with the highest levels seen in moderately differentiated tumors. Receptor mRNA was amplified from the majority of normal (96%) and cancer (94%) samples with an overexpression seen in tumor tissues. Protein expression of prolactin was detected in cancer tissues only, with the highest levels seen in moderately differentiated tumors. Receptor protein expression was correlated with the RT-PCR data, showing up to fourfold overexpression in tumor tissues. Staining for both ligand and receptor was observed in epithelial cells. DNA synthesis was significantly stimulated by prolactin in all cell lines reaching 167-197% of unstimulated controls. CONCLUSION: Expression of prolactin, overexpression of prolactin receptors in colorectal cancers, and mitogenic effects of prolactin suggest a role for this hormone in a subgroup of colorectal cancers, which is presumably mediated by paracrine/autocrine pathways.