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sensitivity indices – the PREDIAS study. Clinical Endocrinology, doi: 10.1111/cen.12811. [Epub ahead of print]. Cal o, L.A., Davis, P.A. & Rossi, G.P. (2014) Understanding the mechanisms of angiotensin II signaling involved in hypertension and its long-term sequelae: insights from Bartter’s and Gitelman’s syndromes, human models of endogenous angiotensin II signaling antagonism. Journal of Hypertension, 32, 2109–2119. Maiolino, G., Azzolini, M., Rossi, G.P. et al. (2015) Bartter/ Gitelman syndromes as a model to study systemic oxidative stress in humans. Free Radical Biology and Medicine. doi: 10.1016/j. freeradbiomed.2015.02.037i [Epub ahead of print]. Davis, P.A., Pagnin, E., Semplicini, A. et al. (2006) Insulin signaling, glucose metabolism, and the angiotensin II signaling system: studies in Bartter’s/Gitelman’s syndromes. Diabetes Care, 29, 469–471. Cal o, L.A. & Pessina, A.C. (2007) RhoA/Rho-kinase pathway: much more than just a modulation of vascular tone. Evidence from studies in humans. Journal of Hypertension, 25, 259–264. Avogaro, A., Pagnin, E. & Calo, L. (2003) Monocyte NADPH oxidase subunit p22(phox)and inducible hemeoxygenase-1 gene expressions are increased in type II diabetic patients: relationship with oxidative stress. The Journal of Clinical Endocrinology and Metabolism, 88, 1753–1759. Pagnin, E., Fadini, G., de Toni, R. et al. (2005) Diabetes induces p66shc gene expression in human peripheral blood mononuclear cells: relationship to oxidative stress. The Journal of Clinical Endocrinology and Metabolism, 90, 1130–1136.
The Authors’ Reply: The association of systemic oxidative stress with insulin resistance: mechanistic insights from studies in Bartter’s and Gitelman’s syndromes We thank Dr Cal o et al. for their comments. Numerous previous studies demonstrated a close association between the activation of renin–angiotensin–aldosterone system (RAAS) and the development of prediabetes and type 2 diabetes mellitus (T2D).1–3 In this respect, accumulated data indicate counterregulatory roles of insulin and angiotensin II involving increased intracellular and systemic oxidative stress. Calo et al. chose the inventive approach to study the relationships between RAAS, T2D and oxidative stress in a cohort of patients with Bartter’s/Gitelman’s syndrome (BS/GS). Despite the activation of RAAS, patients with BS/GS exhibit a normal/low blood pressure and a reduced oxidative stress presumably due to blocking angiotensin II signalling. Moreover, these patients showed a normal glucose tolerance and an increased oral glucose insulin sensitivity index.4 These results obtained from an in vivo human model of low oxidative stress further underline a possible causal relationship between oxidative stress and insulin resistance/sensitivity. Steffi Kopprasch Department of Internal Medicine 3, Technische Universit€at Dresden, University Hospital Carl Gustav Carus, Dresden, Germany E-mail: [email protected] doi: 10.1111/cen.12826 © 2015 John Wiley & Sons Ltd Clinical Endocrinology (2015), 83, 994–1000
References 1 Favre, G.A., Esnault, V.L. & Van Obberghen, E. (2015) Modulation of glucose metabolism by the renin-angiotensin-aldosterone system. American Journal of Physiology. Endocrinology and Metabolism, 308, E435–E449. 2 Saha, S., Bornstein, S.R., Graessler, J. et al. (2015) Crosstalk between glycoxidative modification of low-density lipoprotein, angiotensin II-sensitization, and adrenocortical aldosterone release. Hormone and Metabolic Research, doi: 10.1055/s-0034-1395568. [Epub ahead of print] 3 Sowers, J.R. (2004) Insulin resistance and hypertension. American Journal of Physiology. Heart and Circulatory Physiology, 286, H1597–H1602. 4 Davis, P.A., Pagnin, E., Semplicini, A. et al. (2006) Insulin signaling, glucose metabolism, and the angiotensin II signaling system: studies in Bartter’s/Gitelman’s syndromes. Diabetes Care, 29, 469–471.
Coexistence of Graves’ Disease in a 14-year-old young girl with Gitelman Syndrome Dear Editors, Graves’ disease (GD) is a metabolic syndrome involving an excessive amount of the thyroid hormone and leads to the increased excitability of the nervous, circulatory, digestive and the imbalance of electrolytes including calcium and phosphorus metabolism disorders and low blood potassium. A patient with GD and refractory hypokalaemia was admitted to our hospital. Because thyrotoxic periodic paralysis(TPP), reported primarily in Asian, is a relatively common cause of hypokalaemia in GD, we considered TPP as a complicated diagnosis at first. After treatment with abundant potassium, the serum potassium did not increase. The diagnosis of TPP was questioned, and Gitelman syndrome (GS) was confirmed by clinical and genetic examinations. GS is an autosomal recessive kidney disorder characterized by hypokalaemic metabolic alkalosis with hypocalciuria, hypomagnesaemia, secondary aldosterone system activation and the onset of low blood pressure. This case may offer new insights for endocrinologists to diagnose refractory hypokalaemia. A 14-year-old female patient who suffered from recurrent lower extremity calf pain and fatigue over the past 2 years was diagnosed with hypokalaemia. She was admitted to our department with a serum potassium level of 22 mmol/l on 25 August 2014. The patient was born full-term with a low birthweight at 1980 g. Menarche began at 13 years of age, and the patient had a regular period and normal breast development. Her family members described her as hyperactive with poor learning ability during childhood. She had no history of diuretic and laxative drug use. The clinical examination results showed that her height was 151 cm, and her weight was 38 kg (BMI = 1666 kg/m2). There was no prominent bulging of the eyes, and 2 degrees of bilateral thyroid enlargement existed without tenderness or obvious noise. Her pulse rate was 94 beats per minute without arrhythmia, and the valve area had no pathological murmurs. Blood biochemical analysis showed hypokalaemic metabolic
996 Letters to the Editor alkalosis with hypocalciuria (024 mmol/24 h, n.v.170– 530 mmol/24 h), hypomagnesaemia (053 mmol/l, n.v. 065– 105 mmol/l) and normal serum calcium (245 mmol/l, n.v.225–275 mmol/l). The levels of renin and aldosterone were also increased to 762 ng/ml/h (n.v. 013–190 ng/ml/h), 1915 pg/ml (n.v. 30–170 pg/ml), respectively. Her TSH level was 001 mIU/l (n.v. 027–420 mIU/l), Ft4 level was 9275 pmol/l (n.v.1200–2200 pmol/l), and Ft3 level was 3229 pmol/l (n.v.310–680 pmol/l). TGAb was 29 IU/ml (n.v.00–1150 IU/ml), TPOAb was 1571 IU/ml (n.v. 00– 340 IU/ml), and TSH receptor antibody level increased to 1107 IU/l (n.v. 00–20 IU/l). The radioactive iodine uptake of the thyroid was 51% in 3 h and 65% in 24 h. “Ultrasound results showed the heterogeneous enlargement of the excess thyroid which was one of the symptoms of Graves’ disease (GD).” The average daily blood pressure was 100/51 mmHg. The dynamic electrocardiogram results showed a sinus rhythm, and the average heart rate was 104 bpm with one premature atrial. GD complicated with thyrotoxic periodic paralysis (TPP) was diagnosed according to the laboratory tests. Methimazole was given orally at 30 mg/day. Potassium chloride was given at 3 g/ day via intravenous infusion, and 12 bottles of 10% potassium were orally administered. The serum potassium concentration fluctuated around the level of 25 mmol/l after 1 week of treatment. We corrected our diagnosis as GD combined with GS after clinical and genetic examinations. Genetic detection of peripheral blood specimens found that the SLCl2A3 gene mutation, in which exon 6 in 791 nucleotides with a G to C mutation, resulted in the change of glycine to alanine (G264A). Therefore, the intravenous infusion of potassium chloride was stopped, but oral potassium chloride release tablets (6 g/day), spironolactone (60 mg/day) and potassium–magnesium aspartate (60 ml/day) continued to be administered. Serum potassium levels raised to 3 mmol/l, but the blood magnesium level was still 057 mmol/l after 2 weeks of treatment. Larger doses of spironolactone (80 mg/day) and the original dosages of potassium chloride release tablets (4 g/day) and oral potassium–magnesium aspartate (60 ml/day) were prescribed. On October 23rd, the potassium level rose to 35 mmol/l, and the serum magnesium level rose to 07 mmol/l. On December 30th, thyroid functioning was normal, and methimazole was given orally at 5 mg/day. The symptoms of thyrotoxic periodic paralysis (TPP), including muscle weakness and electrolyte disorders such as severe hypokalaemia, are very similar to those of GS. In this case, the fatigue symptom of hyperthyroidism combined with GS was mistaken for TPP. Clinical manifestations of TPP include reversible electrolyte disorders (serum potassium often
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sensitivity indices – the PREDIAS study. Clinical Endocrinology, doi: 10.1111/cen.12811. [Epub ahead of print]. Cal o, L.A., Davis, P.A. & Rossi, G.P. (2014) Understanding the mechanisms of angiotensin II signaling involved in hypertension and its long-term sequelae: insights from Bartter’s and Gitelman’s syndromes, human models of endogenous angiotensin II signaling antagonism. Journal of Hypertension, 32, 2109–2119. Maiolino, G., Azzolini, M., Rossi, G.P. et al. (2015) Bartter/ Gitelman syndromes as a model to study systemic oxidative stress in humans. Free Radical Biology and Medicine. doi: 10.1016/j. freeradbiomed.2015.02.037i [Epub ahead of print]. Davis, P.A., Pagnin, E., Semplicini, A. et al. (2006) Insulin signaling, glucose metabolism, and the angiotensin II signaling system: studies in Bartter’s/Gitelman’s syndromes. Diabetes Care, 29, 469–471. Cal o, L.A. & Pessina, A.C. (2007) RhoA/Rho-kinase pathway: much more than just a modulation of vascular tone. Evidence from studies in humans. Journal of Hypertension, 25, 259–264. Avogaro, A., Pagnin, E. & Calo, L. (2003) Monocyte NADPH oxidase subunit p22(phox)and inducible hemeoxygenase-1 gene expressions are increased in type II diabetic patients: relationship with oxidative stress. The Journal of Clinical Endocrinology and Metabolism, 88, 1753–1759. Pagnin, E., Fadini, G., de Toni, R. et al. (2005) Diabetes induces p66shc gene expression in human peripheral blood mononuclear cells: relationship to oxidative stress. The Journal of Clinical Endocrinology and Metabolism, 90, 1130–1136.
The Authors’ Reply: The association of systemic oxidative stress with insulin resistance: mechanistic insights from studies in Bartter’s and Gitelman’s syndromes We thank Dr Cal o et al. for their comments. Numerous previous studies demonstrated a close association between the activation of renin–angiotensin–aldosterone system (RAAS) and the development of prediabetes and type 2 diabetes mellitus (T2D).1–3 In this respect, accumulated data indicate counterregulatory roles of insulin and angiotensin II involving increased intracellular and systemic oxidative stress. Calo et al. chose the inventive approach to study the relationships between RAAS, T2D and oxidative stress in a cohort of patients with Bartter’s/Gitelman’s syndrome (BS/GS). Despite the activation of RAAS, patients with BS/GS exhibit a normal/low blood pressure and a reduced oxidative stress presumably due to blocking angiotensin II signalling. Moreover, these patients showed a normal glucose tolerance and an increased oral glucose insulin sensitivity index.4 These results obtained from an in vivo human model of low oxidative stress further underline a possible causal relationship between oxidative stress and insulin resistance/sensitivity. Steffi Kopprasch Department of Internal Medicine 3, Technische Universit€at Dresden, University Hospital Carl Gustav Carus, Dresden, Germany E-mail: [email protected] doi: 10.1111/cen.12826 © 2015 John Wiley & Sons Ltd Clinical Endocrinology (2015), 83, 994–1000
References 1 Favre, G.A., Esnault, V.L. & Van Obberghen, E. (2015) Modulation of glucose metabolism by the renin-angiotensin-aldosterone system. American Journal of Physiology. Endocrinology and Metabolism, 308, E435–E449. 2 Saha, S., Bornstein, S.R., Graessler, J. et al. (2015) Crosstalk between glycoxidative modification of low-density lipoprotein, angiotensin II-sensitization, and adrenocortical aldosterone release. Hormone and Metabolic Research, doi: 10.1055/s-0034-1395568. [Epub ahead of print] 3 Sowers, J.R. (2004) Insulin resistance and hypertension. American Journal of Physiology. Heart and Circulatory Physiology, 286, H1597–H1602. 4 Davis, P.A., Pagnin, E., Semplicini, A. et al. (2006) Insulin signaling, glucose metabolism, and the angiotensin II signaling system: studies in Bartter’s/Gitelman’s syndromes. Diabetes Care, 29, 469–471.
Coexistence of Graves’ Disease in a 14-year-old young girl with Gitelman Syndrome Dear Editors, Graves’ disease (GD) is a metabolic syndrome involving an excessive amount of the thyroid hormone and leads to the increased excitability of the nervous, circulatory, digestive and the imbalance of electrolytes including calcium and phosphorus metabolism disorders and low blood potassium. A patient with GD and refractory hypokalaemia was admitted to our hospital. Because thyrotoxic periodic paralysis(TPP), reported primarily in Asian, is a relatively common cause of hypokalaemia in GD, we considered TPP as a complicated diagnosis at first. After treatment with abundant potassium, the serum potassium did not increase. The diagnosis of TPP was questioned, and Gitelman syndrome (GS) was confirmed by clinical and genetic examinations. GS is an autosomal recessive kidney disorder characterized by hypokalaemic metabolic alkalosis with hypocalciuria, hypomagnesaemia, secondary aldosterone system activation and the onset of low blood pressure. This case may offer new insights for endocrinologists to diagnose refractory hypokalaemia. A 14-year-old female patient who suffered from recurrent lower extremity calf pain and fatigue over the past 2 years was diagnosed with hypokalaemia. She was admitted to our department with a serum potassium level of 22 mmol/l on 25 August 2014. The patient was born full-term with a low birthweight at 1980 g. Menarche began at 13 years of age, and the patient had a regular period and normal breast development. Her family members described her as hyperactive with poor learning ability during childhood. She had no history of diuretic and laxative drug use. The clinical examination results showed that her height was 151 cm, and her weight was 38 kg (BMI = 1666 kg/m2). There was no prominent bulging of the eyes, and 2 degrees of bilateral thyroid enlargement existed without tenderness or obvious noise. Her pulse rate was 94 beats per minute without arrhythmia, and the valve area had no pathological murmurs. Blood biochemical analysis showed hypokalaemic metabolic
996 Letters to the Editor alkalosis with hypocalciuria (024 mmol/24 h, n.v.170– 530 mmol/24 h), hypomagnesaemia (053 mmol/l, n.v. 065– 105 mmol/l) and normal serum calcium (245 mmol/l, n.v.225–275 mmol/l). The levels of renin and aldosterone were also increased to 762 ng/ml/h (n.v. 013–190 ng/ml/h), 1915 pg/ml (n.v. 30–170 pg/ml), respectively. Her TSH level was 001 mIU/l (n.v. 027–420 mIU/l), Ft4 level was 9275 pmol/l (n.v.1200–2200 pmol/l), and Ft3 level was 3229 pmol/l (n.v.310–680 pmol/l). TGAb was 29 IU/ml (n.v.00–1150 IU/ml), TPOAb was 1571 IU/ml (n.v. 00– 340 IU/ml), and TSH receptor antibody level increased to 1107 IU/l (n.v. 00–20 IU/l). The radioactive iodine uptake of the thyroid was 51% in 3 h and 65% in 24 h. “Ultrasound results showed the heterogeneous enlargement of the excess thyroid which was one of the symptoms of Graves’ disease (GD).” The average daily blood pressure was 100/51 mmHg. The dynamic electrocardiogram results showed a sinus rhythm, and the average heart rate was 104 bpm with one premature atrial. GD complicated with thyrotoxic periodic paralysis (TPP) was diagnosed according to the laboratory tests. Methimazole was given orally at 30 mg/day. Potassium chloride was given at 3 g/ day via intravenous infusion, and 12 bottles of 10% potassium were orally administered. The serum potassium concentration fluctuated around the level of 25 mmol/l after 1 week of treatment. We corrected our diagnosis as GD combined with GS after clinical and genetic examinations. Genetic detection of peripheral blood specimens found that the SLCl2A3 gene mutation, in which exon 6 in 791 nucleotides with a G to C mutation, resulted in the change of glycine to alanine (G264A). Therefore, the intravenous infusion of potassium chloride was stopped, but oral potassium chloride release tablets (6 g/day), spironolactone (60 mg/day) and potassium–magnesium aspartate (60 ml/day) continued to be administered. Serum potassium levels raised to 3 mmol/l, but the blood magnesium level was still 057 mmol/l after 2 weeks of treatment. Larger doses of spironolactone (80 mg/day) and the original dosages of potassium chloride release tablets (4 g/day) and oral potassium–magnesium aspartate (60 ml/day) were prescribed. On October 23rd, the potassium level rose to 35 mmol/l, and the serum magnesium level rose to 07 mmol/l. On December 30th, thyroid functioning was normal, and methimazole was given orally at 5 mg/day. The symptoms of thyrotoxic periodic paralysis (TPP), including muscle weakness and electrolyte disorders such as severe hypokalaemia, are very similar to those of GS. In this case, the fatigue symptom of hyperthyroidism combined with GS was mistaken for TPP. Clinical manifestations of TPP include reversible electrolyte disorders (serum potassium often
