Musculoskeletal pain and muscular weakness as the main symptoms of adult hypophosphatasia in a Spanish cohort: clinical characterization and identification of a new ALPL gene variant.

INTRODUCTION: Hypophosphatasia (HPP) is a rare inherited disorder, caused by mutations in the alkaline phosphatase (ALPL) gene, which encodes for the tissue non-specific alkaline phosphatase (TNSALP) isoform of alkaline phosphatase (ALP). Adult HPP is one of the mild forms that presents with unspecific signs such as osteopenia, osteomalacia and muscle involvement. Our purpose was to identify and characterize possibly misdiagnosed adult HPP patients at a clinical and biochemical level. MATERIAL AND METHODS: At the laboratory of Miguel Servet University Hospital we retrospectively reviewed serum ALP levels in adults over a 48-month period. The clinical records of individuals with consistently low ALP levels were reviewed to exclude secondary causes. Those with persistent hypophosphatasemia were screened for symptoms of HPP. The study participants were evaluated at biochemical and genetic levels. RESULTS: We identified 705 ALP determinations (out of 384,000 processed) in 589 patients below the reference range (30 U/l). Only 21 patients with clinical signs and symptoms of HPP were selected for genetic testing. Finally, only 12 patients participated in the study, 83.3% of whom (10/12) harbored a pathogenic or likely pathogenic variant in a heterozygous state. The major symptoms of our cohort were the presence of musculoskeletal pain (100% of patients) and muscular weakness (83.3% patients). CONCLUSION: Mild HPP patients presenting with diffuse symptoms such as musculoskeletal pain may be undiagnosed or misdiagnosed as osteoporosis patients by routine diagnosis. It is important to identify these individuals, to avoid inappropriate treatment with antiresorptive drugs.

Effects of antidiabetic drugs on bone metabolism.

Objectives: The prevalence of diabetes mellitus type 2 (DMT2) is increasing exponentially worldwide. DMT2 patients have been found to be at a higher risk for bone fractures than the healthy population. Hence, improving our understanding of the impact of antidiabetic drugs on bone metabolism is crucial. Methods: A descriptive, retrospective study involving 106 patients receiving six groups of antidiabetic drugs: insulin; dipeptidylpeptidase four inhibitors (DPP4i); glucagon-like peptide type 1 receptor agonists (GLP1ra); sulfonylureas; sodium-glucose cotransporter two inhibitors (SGLT2i); and pioglitazone, in which osteocalcin (OC), bone alkaline phosphatase (BAP) and C-terminal telopeptide of collagen type 1 or beta-crosslaps (ß-CTx) were determined. Results: ß-CTx concentrations were higher in the patients treated with pioglitazone, as compared to patients treated with DPP4i (p=0.035), SGLT2i (p=0.020) or GLP1ra (p<0.001). The lowest ß-CTx concentrations were observed in the patients treated with GLP1ra. Conclusions: Bone remodeling is influenced by the type of antidiabetic drug administered to DMT2 patients. In our study, the patients who received pioglitazone showed higher ß-CTx concentrations, as compared to patients treated with other types of antidiabetic drugs. This finding highlights the convenience of avoiding these drugs, especially in postmenopausal women with DMT2. GLP1ra drugs were associated with the lowest ß-CTx concentrations, which suggests that these agents could exert beneficial effects on bone metabolism.

Retinochoroidal Vascular Changes in Long-Term Type 1 Diabetic Patients Assessed by Optic Coherence Tomography Angiography.

To study retinal and choriocapillaris (CC) alterations using optical coherence tomography angiography (OCTA) in long-term type 1 diabetic (DM1) patients without diabetic retinopathy (DR). Seventy-eight eyes from 78 well-controlled DM1 patients diagnosed at least 15 years prior and 130 eyes of 130 healthy subjects were included in a cross-sectional descriptive study. Six eyes were excluded from the DM1 group. OCTA with Deep Range Imaging (DRI)-Triton swept source (SS)-OCT was performed. Statistically significant differences were found in all areas of the superficial capillary plexus (SCP), with lower values in DM1 patients. Differences were noted in all quadrants of the deep capillary plexus (DCP) except for the central area. Significant changes in CC blood flow were only found in the center. The foveal avascular zone (FAZ) area and diameters in the SCP were significantly different, while the DCP FAZ area was similar in both groups. Disease duration and microalbuminuria correlated negatively with some SCP areas and positively with FAZ values. Anatomical evaluation revealed microaneurysms in both plexuses, FAZ modifications, and areas lacking blood perfusion. Long-term type 1 diabetic patients without DR display microvascular abnormalities affecting retinal and CC blood perfusion, along with anatomical changes in retinal blood vessels.

Electrophysiological findings in long-term type 1 diabetes patients without diabetic retinopathy using different ERG recording systems.

To assess full-field electroretinogram findings in long-term type 1 diabetes patients without diabetic retinopathy. Prospective study including 46 eyes of 23 patients with type 1 diabetes and 46 age-matched healthy eyes evaluated by the RETI-port/scan21 and the portable system RETeval following ISCEV guidelines. The average duration of diabetes was 28.88 ± 8.04 years. In scotopic conditions, using the RETI-port/scan21, diabetic patients showed an increase in b-wave implicit time (IT) (p = 0.017) with the lowest stimuli; a diminished b-wave amplitude (p = 0.005) in the mixed response, an increased IT (p = 0.004) with the high-intensity stimuli and an OP2 increased IT (p = 0.008) and decreased amplitude (p = 0.002). Under photopic conditions, b-wave amplitude was lower (p < 0.001) and 30-Hz flicker response was diminished (p = 0.021). Using the RETeval, in scotopic conditions, diabetic patients showed a reduction in the rod b-wave amplitude (p = 0.009), an increase in a-wave IT with the 280 Td.s stimulus (p = 0.005). OP2 had an increased IT and diminished amplitude (p = 0.003 and p = 0.002 respectively). 16 Td.s flicker showed an increased IT (p = 0.008) and diminished amplitude (p = 0.048). Despite variations in values between both systems, nearly all results displayed positive correlations. Long-term type 1 diabetes patients without diabetic retinopathy exhibit alterations in scotopic conditions, as evidenced by both conventional and portable electroretinogram devices. These findings suggest a modified retinal function, particularly in rod-driven pathways, even in the absence of vascular signs.

Retinal Function in Long-Term Type 1 Diabetes without Retinopathy: Insights from Pattern Electroretinogram and Pattern Visual Evoked Potentials Assessments.

BACKGROUND: To evaluate changes in pattern electroretinogram (pERG) and pattern visual evoked potentials (pVEP) in patients with long-lasting type 1 diabetes without diabetic retinopathy (DR). METHODS: Prospective study involving 92 eyes divided into two groups. The diabetic group included 46 eyes of 23 patients with type 1 diabetes (T1DM); the control group included 23 age-matched healthy subjects. pERG and pVEP were assessed using the RETI-port/scan21 recording software (version 1021.3.0.0). RESULTS: Mean age was 48 ± 9.77 years for the diabetic group and 51.7 ± 4.75 years for the control group. The mean duration of diabetes was 28.88 ± 8.04 years. The mean HbA1c value was 7.29 ± 0.89%. There were no differences in the age or sex distribution. Regarding the pERG, T1DM patients exhibited a significant decrease in the amplitude of the P50 and N95 waves compared to the control group (p = 0.018 and p = 0.035, respectively), with no differences in the peak time of each component. pVEP showed no significant changes in either peak time or amplitude of the different components. CONCLUSIONS: Long-term T1DM patients without DR showed changes in the amplitude of pERG waves with preserved peak times. We did not observe modifications in pVEP. pERG may serve as a subclinical marker of ganglion cell damage in long-term T1DM patients.

A comparison of induced effects on urinary calcium by thiazides and different dietary salt doses: Implications in clinical practice. / Comparación de los efectos inducidos sobre la calciuria por tiazidas y diferentes dosis de sal en la dieta: implicaciones en la práctica clínica.

INTRODUCTION: Both dietary restriction of sodium chloride (NaCl) and treatment with thiazides have been used in hypercalciuric patients. OBJECTIVES: To calculate regular salt intake and investigate the correlation between natriuresis and urinary calcium with usual diet (B) and after changing the amount of NaCl intake and administration of thiazides. MATERIAL AND METHODS: Nineteen healthy young individuals had their diet replaced by 2l of Nutrison® Low Sodium (500mg sodium/day) daily for two days. Then, 5g of NaCl were added every two days («5¼, «10¼ and «15¼), administering 50mg (H50) and 100mg (H100) of Higroton® on the last two days. Blood sodium, plasma renin activity (PRA) and aldosterone were determined in venous blood samples, as were urinary sodium and calcium. STATISTICAL ANALYSIS: Wilcoxon t-test and the Pearson linear correlation were calculated. RESULTS: Urinary Na (mEq/24h): 210.3±87.6 («B¼); 42.7±20.4 («5¼); 135.5±50.6 («10¼); 225.5±56.7 («15¼). Urinary calcium (mg/24h): 207.8±93.6 («B¼); 172.8±63.1 («5¼); 206.2±87.7 («10¼); 227.4±84.1 («15¼). A positive correlation was observed between natriuresis and urinary calcium in «10¼ (r=0.47) and «15¼ (r=0.67). After Higroton®, natriuresis: 232.3±50.7; 377±4 (H50); 341.1±68.4 (H100); Ca in urine: 209.8±57.4; 213.2±67.6 (H50); 159.1±52.2 (H100). CONCLUSIONS: Salt intake in the population studied was estimated to be 14.9±4.9g/day with a positive correlation found between sodium and calcium urine output with daily intakes of 11.25 and 16.25g of salt. With the usual intake, for each gram of salt, urinary calcium increased by 5.46 mg/24 h and with 100mg of Higroton® it decreased by 50.7mg/24h. These data could be useful for the management of patients with excretory hypercalciuria or hypoparathyroidism.

Comparación de los efectos inducidos sobre la calciuria por tiazidas y diferentes dosis de sal en la dieta: implicaciones en la práctica clínica / A comparison of induced effects on urinary calcium by thiazides and different dietary salt doses: Implications in clinical practice

Introducción: La restricción de ClNa en la dieta y el tratamiento con tiazidas han sido utilizados en pacientes hipercalciúricos. Objetivos: Conocer la ingesta habitual de sal y la correlación entre natriuria y calciuria con la dieta habitual (B) y tras la modificación de la cantidad de ClNa y la administración de tiazidas. Material y métodos: Diecinueve jóvenes sanos, a los que se les sustituyó su dieta por 2 l diarios de Nutrison(R) Low Sodium (500 mg de Na) durante 2 días. Posteriormente se añadieron cada 2 días 5 g de ClNa ("5", "10" y "15") y durante los 2 últimos días 50 y 100 mg de Higrotona(R) (H50) y (H100). Se determinaron iones, ARP y aldosterona en sangre venosa, así como la natriuria y calciuria. Valoración estadística: se calcula la t de Wilcoxon y la correlación lineal de Pearson. Resultados: Natriuria (mEq/24h): 210,3 ± 87,6 ("B"); 42,7 ± 20,4 ("5"); 135,5 ± 50,6 ("10"); 225,5 ± 56,7 ("15"). Calciuria (mg/24h): 207,8 ± 93,6 ("B"); 172,8 ± 63,1 ("5"); 206,2 ± 87,7 ("10"); 227,4 ± 84,1 ("15"). Correlación positiva entre natriuria y calciuria en "10" (r = 0,47) y en "15" (r = 0,67). Tras Higrotona(R), natriuria: 232,3 ± 50,7; 377 ± 4 (H50); 341,1 ± 68,4 (H100); Ca en orina: 209,8 ± 57,4; 213,2 ± 67,6 (H50); 159,1 ± 52,2 (H100). Conclusiones: La ingesta de sal en la población estudiada es de 14,9 ± 4,9 g/día. Encontramos correlación entre natriuria y calciuria con ingestas de 11,25 y 16,25 g de sal. Con la ingesta habitual, por cada gramo de sal aumenta la calciuria 5,46 mg y con 100 mg de Higrotona(R), la calciuria disminuye 50,7 mg/24 h. Los datos podrían ser de utilidad para el manejo de pacientes con hipercalciuria excretora o hipoparatiroidismo

Introduction: Both dietary restriction of sodium chloride (NaCl) and treatment with thiazides have been used in hypercalciuric patients. Objectives: To calculate regular salt intake and investigate the correlation between natriuresis and urinary calcium with usual diet (B) and after changing the amount of NaCl intake and administration of thiazides. Material and methods: Nineteen healthy young individuals had their diet replaced by 2l of Nutrison(R) Low Sodium (500 mg sodium/day) daily for two days. Then, 5 g of NaCl were added every two days ("5", "10" and "15"), administering 50 mg (H50) and 100 mg (H100) of Higroton(R) on the last two days. Blood sodium, plasma renin activity (PRA) and aldosterone were determined in venous blood samples, as were urinary sodium and calcium. Statistical analysis: Wilcoxon t-test and the Pearson linear correlation were calculated. Results: Urinary Na (mEq/24h): 210.3 ± 87.6 ("B"); 42.7±20.4 ("5"); 135.5±50.6 ("10"); 225.5±56.7 ("15"). Urinary calcium (mg/24h): 207.8±93.6 ("B"); 172.8±63.1 ("5"); 206.2±87.7 ("10"); 227.4±84.1 ("15"). A positive correlation was observed between natriuresis and urinary calcium in "10" (r = 0.47) and "15" (r = 0.67). After Higroton(R), natriuresis: 232.3 ± 50.7; 377 ± 4 (H50); 341.1±68.4 (H100); Ca in urine: 209.8 ± 57.4; 213.2 ± 67.6 (H50); 159.1 ± 52.2 (H100). Conclusions: Salt intake in the population studied was estimated to be 14.9 ± 4.9 g/day with a positive correlation found between sodium and calcium urine output with daily intakes of 11.25 and 16.25g of salt. With the usual intake, for each gram of salt, urinary calcium increased by 5.46 mg/24 h and with 100 mg of Higroton(R) it decreased by 50.7 mg/24h. These data could be useful for the management of patients with excretory hypercalciuria or hypoparathyroidism

Leptina e insulinoterapia en la diabetes gestacional / Leptin and insulin therapy in gestational diabetes

Introducción: Se han publicado varios trabajos que implican a la leptina (L) en diversos procesos metabólicos, entre ellos la diabetes gestacional (DG) y otras alteraciones del embarazo como la preeclampsia y el retraso de crecimiento intrauterino. Se ha observado que la concentración de L en plasma es superior en gestantes diabéticas que en gestantes sanas. Objetivo: Valorar si la L puede ser un parámetro bioquímico de utilidad en pacientes con DG a la hora de predecir la necesidad de tratamiento insulínico desde el momento mismo del diagnóstico. Pacientes y método: Cincuenta mujeres diagnosticadas de DG entre las semanas 28 y 32 con: media ± desviación estándar de edad, 34,4 ± 4,5 años; IMC, 25,4 ± 2,14, y L, 48,5 ± 16 ng/ml. Fueron separadas en 2 grupos: uno con criterios de insulinización, formado por 24 pacientes, y otro que no precisó insulina, formado por 26. Los criterios de inclusión fueron: presentar un IMC > 22,5 y 40 ng/ml. Conclusiones: Con la cautela de precisar más estudios y con mayor número de pacientes, se puede indicar que la L es útil como parámetro bioquímico que nos ayude a predecir la necesidad de tratamiento insulínico en pacientes diagnosticadas de DG

Introduction: Various studies have implicated leptin in several metabolic processes, among them gestational diabetes (GD) and other pregnancy-associated alterations such as preeclampsia and uterine growth retardation. Plasma leptin levels have been observed to be higher in diabetic pregnant women than in healthy pregnant women. Objective: To evaluate whether leptin could be a useful biochemical marker in patients with GD to predict the need for insulin therapy at diagnosis. Patients and method: Fifty women with a diagnosis of GD between 28 and 32 weeks of pregnancy [mean age, 34.4 ± 4.5 years; body mass index (BMI), 25.4 ± 2.14, and leptin level, 48.5 ± 16 ng/ml] were studied. The women were divided into two groups: one group was composed of 24 women with criteria for insulin therapy and the other group consisted of 26 women not requiring insulin therapy. The inclusion criteria were BMI greater than 22.5 and lower than 27 and biochemical determination between weeks 28 and 32. Results: Maternal plasma leptin levels were significantly higher in the group requiring insulin. No differences were found in the mean age of the patients or in BMI. The odds ratio predicting the need for insulin therapy during pregnancy was 6 in pregnant women with a leptin level higher than 40 ng/ml. Conclusions: Leptin determination could be useful in predicting the need for insulin therapy in patients with GD. However, further studies with a larger number of patients are required to confirm our findings