The water deprivation test and a potential role for the arginine vasopressin precursor copeptin to differentiate diabetes insipidus from primary polydipsia.

The water deprivation test is the gold standard test to differentiate central or nephrogenic diabetes insipidus (DI) from primary polydipsia (PP) in patients with polyuria and polydipsia. Few studies have addressed the diagnostic performance of this test. The aim of this retrospective cohort study was to evaluate the diagnostic performance of the standard water deprivation test, including plasma arginine vasopressin (AVP) measurements, in 40 consecutive patients with polyuria. We compared initial test results with the final clinical diagnosis, i.e., no DI, central DI, or nephrogenic DI. The median length of follow-up was 8 years. In a subset of ten patients, the novel marker copeptin (CP) was measured in plasma. Using the final diagnosis as a gold standard, a threshold for urine osmolality of >800 mOsmol/kg after water deprivation yielded a sensitivity and specificity of 96 and 100%, respectively, for diagnosing PP. Sensitivity increased to 100% if the cut-off value for urine osmolality was set at 680 mOsmol/kg. Plasma AVP levels did not differ between patient groups and did not differentiate among central DI, nephrogenic DI, or PP. In all three patients with central DI, plasma CP was <2.5 pmol/l with plasma osmolality >290 mOsmol/kg, and >2.5 pmol/l in patients without DI. The optimal cut-off value for differentiating PP from DI during a water deprivation test was urine osmolality >680 mOsmol/kg. Differentiating between central and nephrogenic DI should be based on clinical judgment as AVP levels did not discriminate.

Familial neurohypophyseal diabetes insipidus due to a novel mutation in the arginine vasopressin-neurophysin II gene.

BACKGROUND: Familial neurohypophyseal (central) diabetes insipidus (DI) is caused by mutations in the arginine vasopressin-neurophysin II (AVP-NPII) gene. The majority of cases is inherited in an autosomal dominant way. In this study, we present the clinical features of a mother and her son with autosomal dominant neurohypophyseal DI caused by a novel mutation. CASE: A thirty-four-year-old woman and her three-year-old son were evaluated because of polyuria and polydipsia since the age of 1.5 years onwards. Both patients were subjected to a water deprivation test confirming the diagnosis of central DI. Magnetic resonance imaging of the brain of the mother showed a hypothalamus without apparent abnormalities and a relatively small neurohypophysis without a hyperintense signal. Mutation analysis showed a c.322G>T (p.?/p.Glu108X) in Exon 2 of the AVP-NPII gene in both mother and son. DISCUSSION: This study reports neurohypophyseal DI in a mother and her son due to a novel mutation in Exon 2 of the AVP-NPII gene. Clinical and pathophysiological aspects of this disease are shortly reviewed and discussed.

Different dose-dependent correction of MIP-1beta and chitotriosidase during initial enzyme replacement therapy.

In tissue lesions of type I Gaucher patients, characteristic lipid-laden macrophages, 'Gaucher cells', are surrounded by inflammatory phagocytes. Gaucher cells secrete the elevated plasma chitotriosidase. The elevated plasma MIP-1beta in Gaucher patients stems from the phagocytes surrounding the Gaucher cells. Plasma chitotriosidase and MIP-1beta decrease upon successful enzyme replacement therapy (ERT) with mannose-terminated recombinant glucocerebrosidase (alglucerase). Previous histochemical analysis of Gaucher spleens revealed that Gaucher cells express little mannose receptor, in contrast to surrounding phagocytes. We therefore investigated the corrective effects of ERT on plasma MIP-1beta and chitotriosidase in more detail. We also compared effects of one year of treatment with a relatively low dose and a relatively high dose of ERT. A more rapid correction in plasma MIP-1beta, compared to chitotriosidase, was observed in most patients on low-dose ERT. Correction of plasma MIP-1beta and chitotriosidase levels was more pronounced in the higher-dosed patient group. Upon prolonged treatment, differences in the effects of enzyme dose were no longer significant. Normalization of plasma MIP-1beta and chitotriosidase levels was attained in the majority of patients. In conclusion, ERT with mannose-terminated gluocerebrosidase results in prominent corrections of plasma chitotriosidase, a marker of Gaucher cells, and in particular of plasma MIP-1beta, a marker of inflammatory phagocytes. The sharper response in plasma MIP-1beta to ERT is in line with the observation that especially phagocytes surrounding Gaucher cells express mannose-receptors.

Low HDL cholesterol levels in type I Gaucher disease do not lead to an increased risk of cardiovascular disease.

OBJECTIVE: A low plasma high-density lipoprotein cholesterol (HDL-c) concentration is an important risk factor for the development of atherosclerotic cardiovascular disease. HDL-c levels are abnormally low in type I Gaucher disease (GD) patients. The aim of this study was to determine whether GD is associated with premature atherosclerosis. METHODS: Lipid profiles, apolipoproteins, and carotid artery intima-media thickness (cIMT) were analyzed in 40 type I GD patients, 34 carriers and 41 control subjects. cIMT is a non-invasive validated biomarker for the status of atherosclerosis and present and future cardiovascular disease risk. RESULTS: Compared to control subjects, patients showed decreased HDL-c (1.1+/-0.3 mmol/L) as well as mildly decreased low-density lipoprotein cholesterol (LDL-c) levels (2.8+/-0.7 mmol/L), with an increased ApoB/ApoA1 ratio. In carriers, HDL-c levels were normal, but LDL-c levels were decreased (2.7+/-0.8 mmol/L). Mean cIMT measurements were not different in the three study groups (patients: 0.63+/-0.1mm versus carriers: 0.64+/-0.1mm versus control subjects: 0.65+/-0.1 mm). CONCLUSION: In Gaucher disease low HDL-c levels do not lead to premature atherosclerosis as assessed by cIMT measurement. This indicates that the inverse relationship between levels of HDL-c and risk of cardiovascular disease in the general population may not be present in all conditions characterised by low HDL-c levels.

Immunoglobulin and free light chain abnormalities in Gaucher disease type I: data from an adult cohort of 63 patients and review of the literature.

Gaucher disease type I, the most common lysosomal storage disorder, is associated with immunoglobulin abnormalities. We studied the prevalence, risk factors, pathogenesis, and effect of enzyme relation therapy (ERT) on gammopathies in an adult Gaucher disease type I cohort (N = 63) and related the results to a review of the currently available literature. Polyclonal gammopathies and monoclonal gammopathy of undetermined significance (MGUS) in our adult GD I cohort were found in 41% and 19% of patients. These results are similar to the data from the literature and correspond to the increased risk of multiple myeloma (MM) that has been described. The prevalence of MGUS in our cohort increased with age but was not associated with disease severity or exposure time. The serum levels of free light chains of immunoglobulins were measured and were not found predictive for the development of MGUS or MM. Levels of pro- as well as anti-inflammatory cytokines, growth factors, and chemokines, especially those involved in inflammation and B-cell function, are disturbed in GD I, with the most impressive and consisting elevations for interleukin-10 and pulmonary and activation-regulated chemokine. A beneficial effect of ERT on the occurrence and progression of gammopathies was suggested from longitudinal data.

Overweight, insulin resistance and type II diabetes in type I Gaucher disease patients in relation to enzyme replacement therapy.

Type I Gaucher disease, a lysosomal storage disorder is associated with metabolic abnormalities such as high resting energy expenditure, low circulating adiponectin and peripheral insulin resistance. Treatment with enzyme replacement therapy (enzyme therapy) leads to a decrease in resting energy expenditure, but its influence on weight and risk of development of type II diabetes is unknown. We studied the BMI, prevalence of overweight, insulin resistance and type II diabetes in untreated and enzyme therapy treated Gaucher patients before and after several years of follow-up and compared this to data on healthy subjects from literature. We established that in untreated Gaucher patients the prevalence of overweight is lower than in the general population. Long-term treatment with enzyme therapy induces a larger than average weight gain leading to a similar prevalence of overweight in enzyme therapy treated patients and the general population. The prevalence of type II diabetes increases significantly during treatment with enzyme therapy, resulting in a comparable prevalence of type II diabetes in enzyme therapy treated patients and the general population.

Release of granzymes and chemokines in Thai patients with leptospirosis.

The plasma concentrations of granzymes are considered to reflect the involvement of cytotoxic T-cells and natural killer cells in various disease states. Interferon (IFN)-gamma-inducible protein-10 (IP-10) and monokine induced by IFN-gamma (Mig) are members of the non-ELR CXC chemokine family that act on T-cells and natural killer cells. This study revealed that the plasma concentrations of granzyme B (but not granzyme A), IP-10 and Mig were higher in 44 Thai patients with definite or possible leptospirosis than in healthy blood donors. These data suggest that activation of cell-mediated immunity is part of the early host response to leptospirosis.

Increased incidence of cancer in adult Gaucher disease in Western Europe.

The adult form of Gaucher disease (type I GD) is associated with a high prevalence of hypergammaglobulinemia and monoclonal gammopathy of undetermined significance (MGUS). A significantly increased risk of cancer, especially of hematological types, has been found in Ashkenazi-Jewish GD type 1 patients. In this study, incidence and mortality of cancer were assessed in a total of 131 GD patients of mixed ancestry in a population from Western Europe, i.e. 2 Gaucher referral centers in Germany (Düsseldorf) and the Netherlands (Amsterdam). Standardized rate ratios were determined by indirect standardization, using age- and sex-specific incidence and mortality rates of the Dutch population. A total of 14 GD patients of non-Ashkenazi-Jewish descent were identified of whom 5 had a hematologic malignancy. These numbers correspond to an increased risk of cancer of 2.5 (95% CI 1.1-4.7) and an increased risk of hematologic cancer of 12.7 (95% CI 2.6-37.0) among GD patients compared to the general population. In particular, the incidences of multiple myeloma and hepatocellular carcinoma in absence of preexisting cirrhosis were highly elevated, with standardized rate ratios of 51.1 (95% CI 6.2-184) and 141.3 (95% CI 17.1-510.5), respectively. These strongly increased risks on developing cancer suggest that measures for early detection and prevention of hematological and hepatic malignancies in patients with Gaucher type I disease are mandatory.

Gaucher disease: from fundamental research to effective therapeutic interventions.

Gaucher disease type I is the most common lysosomal storage disorder, with a prevalence of 1:50,000 in most countries. It is caused by an autosomally recessive inherited deficiency of the lysosomal enzyme glucocerebrosidase, leading to the accumulation of glucocerebroside in the macrophages. The lipid-laden macrophages are called Gaucher cells and can be found in the liver, spleen and bone marrow. Gaucher disease type I should be considered in any patient with an unexplained splenomegaly with or without bleeding diathesis, skeletal manifestations or hepatomegaly. The diagnosis is made by showing decreased glucocerebrosidase activity in peripheral blood leucocytes or by demonstrating previously defined DNA mutations. Detailed knowledge about the molecular defect has provided a rationale for therapeutic interventions and attempts have been made to correct the defect at gene level, protein level and by manipulation of metabolism. Clinical trials of gene therapy have been conducted but so far have not resulted in successful intervention. For moderate to severely affected patients, intravenous enzyme supplementation therapy is the treatment of choice, resulting in substantial clinical improvement in the majority of patients. For individuals with mild Gaucher disease, an oral substrate inhibitor can also be considered if intravenous treatment is a less attractive option.