Euglycemic Ketoacidosis in a Patient without Diabetes Taking Sodium-Glucose Cotransporter 2 Inhibitors for Heart Failure.

BACKGROUND Sodium-glucose cotransporter 2 (SGLT2) inhibitors are used to improve the prognosis of patients with diabetes, heart failure, or chronic kidney disease. The use of SGLT2 inhibitors in patients without diabetes is expected to increase. Diabetic ketoacidosis is a severe complication of SGLT2 inhibitors in patients with diabetes. People without diabetes are thought to be less likely to develop ketoacidosis, and reports of SGLT2 inhibitor-induced ketoacidosis are uncommon in people without diabetes. CASE REPORT Herein, we describe a case of ketoacidosis in an 83-year-old Japanese woman without diabetes who was administered SGLT2 inhibitors for heart failure (ejection fraction: approximately 30%). Two weeks prior to admission, she had suffered a vertebral fracture and rib fracture due to a fall, which was followed by anorexia, but she continued to take SGLT2 inhibitors. On admission, blood test results revealed a blood glucose level of 124 mg/dL, hemoglobin A1C level of 5.9%, pH of 7.329, HCO3⁻ concentration of 14.3 mmol/L, and a ß-hydroxybutyrate concentration of 5150 µmol/L, leading to a diagnosis of euglycemic ketoacidosis. The patient's C-peptide level was consistent with the blood glucose levels on admission, indicating that she had adequate insulin secretion. The patient was treated only with glucose administration without insulin and was discharged after discontinuation of the SGLT2 inhibitor. CONCLUSIONS This case illustrates that patients with or without diabetes may develop SGLT2 inhibitor-related ketoacidosis after several days of inadequate food intake; therefore, patients should be informed of this risk.

Inflammation Related to Association of Low Uric Acid and Progression to Severe Disease in Patients Hospitalized for Non-Severe Coronavirus Disease 2019.

Uric acid has antioxidant properties. To examine whether a low uric acid level is associated with severe coronavirus disease 2019 (COVID-19) progression via inflammation, alveolar damage, and/or coagulation abnormality, a retrospective observational study of 488 patients with non-severe COVID-19 and serum uric acid level ≤7 mg/dL at admission was conducted. Serum C-reactive protein (CRP), serum Krebs von den Lungen 6 (KL-6), and plasma D-dimer levels were also measured as markers of inflammation, alveolar damage, and coagulation abnormality, respectively. Median values for uric acid, CRP, KL-6, and D-dimer at admission were 4.4 mg/dL, 3.33 mg/dL, 252.0 U/mL, and 0.8 µg/mL, respectively. Among the total cohort, 95 (19.5%) progressed to severe COVID-19 with a median (interquartile range) time of 7 (4-14) days. Multivariable Cox proportional hazards regression analysis showed that low uric acid level was associated with a higher rate of severe COVID-19 progression. However, uric acid level was inversely associated with CRP level, and the association between the level of uric acid and severe COVID-19 progression was significantly different with and without CRP level inclusion. In contrast, no such association was found for KL-6 or D-dimer level. Low uric acid may contribute to severe COVID-19 progression via increased inflammation in subjects without hyperuricemia.

Glycated hemoglobin level on admission associated with progression to severe disease in hospitalized patients with non-severe coronavirus disease 2019.

AIMS/INTRODUCTION: Poor glycemic control is known to be associated with severe infection development. This retrospective observational study examined whether glycemic control before coronavirus disease 2019 (COVID-19) onset contributes to progression from non-severe to severe COVID-19. MATERIALS AND METHODS: Glycated hemoglobin (HbA1c) was measured on hospital admission in 415 patients with non-severe COVID-19. The outcome was determined from time of hospital admission to severe progression, based on clinical practice guidelines for COVID-19 in Japan. RESULTS: The median value for HbA1c on admission was 6.1%, with diabetes present in 138 patients (33.3%). Among the total cohort, 93 (22.4%) progressed to severe COVID-19 with a median (interquartile range) time of 4 days (3-7 days), whereas 322 (77.6%) were discharged after 13 days (10-17 days). A multivariable Cox proportional hazards regression model showed that HbA1c level on admission was independently associated with progression to severe COVID-19 (hazard ratio for 1% increase 1.237, 95% confidence interval 1.037-1.475; P = 0.018), with findings consistent among several sensitivity analyses. In subgroup analyses, such an association was significant in patients with diabetes, as well as older age, current smoking habit, lower estimated glomerular filtration rate, higher C-reactive protein level, moderate II COVID-19, dyslipidemia and chronic respiratory disease, with no remarkable inconsistency among the subgroups. Finally, higher HbA1c level (≥7%) was more strongly associated with severe COVID-19 progression than diabetes. CONCLUSIONS: The results suggest that poor glycemic control before COVID-19 onset contributes to progression from non-severe to severe COVID-19, even in patients with severe COVID-19 risk factors regardless of the presence of diabetes.

Addison's Disease Caused by Tuberculosis with Atypical Hyperpigmentation and Active Pulmonary Tuberculosis.

We herein report a case of Addison's disease caused by tuberculosis characterized by atypical hyperpigmentation, noted as exacerbation of the pigmentation of freckles and the occurrence of new freckles, that was diagnosed in the presence of active pulmonary tuberculosis. The clinical condition of the patient was markedly ameliorated by the administration of hydrocortisone and anti-tuberculosis agents. When exacerbation of the pigmentation of the freckles and/or the occurrence of new freckles are noted, Addison's disease should be considered as part of the differential diagnosis. In addition, the presence of active tuberculosis needs to be assumed whenever we treat patients with Addison's disease caused by tuberculosis, despite its rarity.

Effects of rapid-acting insulin analogues insulin glulisine and insulin aspart on postprandial glycemic excursion with single bout of exercise in patients with type 2 diabetes.

The analogue insulin glulisine (Glu) shows both more rapid onset and shorter duration of action compared with the other rapid-acting insulin analogues. The current study investigates these properties in regard to the occurrence of hypoglycemia related to exercise. A randomized, single-center, open-label, crossover study was conducted in 12 hospitalized type 2 diabetes patients (all male, mean ± SD age of 51.9 ± 11.3 years; BMI: 25.5 ± 3.9 kg/m2; HbA1c: 11.2 ± 2.4 %). Glu or insulin aspart (Asp) was subcutaneously administered just before breakfast. Insulin dosage was determined as the usual dose of pre-prandial rapid-acting insulin for patients treated with insulin therapy or as 0.1 unit/kg for patients treated with oral anti-hyperglycemic agents. Sixty min after the start of eating, the patients began aerobic exercise on a bicycle ergometer for 30 min at 50% of maximum heart rate. Hypoglycemic episodes (plasma glucose level < 70 mg/dL with or without symptoms) were observed more frequently in Asp group (p < 0.05). Post-exercise plasma glucose levels at 90, 120, and 150 min were significantly lower in Asp group (p < 0.05). In patients with BMI < 25 kg/m2 (n = 6), post-exercise blood glucose levels were significantly lower in Asp group (p < 0.05), while in patients with BMI ≥ 25 kg/m2 (n = 6) the difference was not significant. Glu may therefore be a suitable choice of rapid-acting insulin for patients with type 2 diabetes who are at high risk of post-exercise hypoglycemia.

Sitagliptin reduces the urine albumin-to-creatinine ratio in type 2 diabetes through decreasing both blood pressure and estimated glomerular filtration rate.

BACKGROUND: We investigated the change in the urine albumin-to-creatinine ratio (ACR) to examine the effect of sitagliptin on diabetic nephropathy. METHODS: Sitagliptin at a dose of 50 mg was administered to 247 outpatients with type 2 diabetes. Data were collected on the patients' laboratory results (including the ACR), blood pressure, and body weight. Clinical data were compared before and after 3 months' administration of sitagliptin. RESULTS: The ACR changed from 150.0 ± 538.6 mg/gCre to 148.3 ± 764.6 mg/gCre over 3 months. In the patients with micro- and macro-albuminuria, the ACR after 3 months significantly decreased compared with the baseline (P = 0.04 and P = 0.02, respectively). The subjects whose ACR decreased experienced significantly larger decreases over the 3-month period in blood pressure and estimated glomerular filtration rate (eGFR) than the other subjects. There was no significant correlation between change in ACR (ΔACR) and change in hemoglobin A1c (ΔHbA1c) during 3 months (r = 0.04, P = 0.59), but there was a significant correlation between change in ΔACR and change in systolic blood pressure (r = 0.16, P = 0.03). Multiple regression analysis revealed that the significant predictors for ΔACR were change in systolic blood pressure (ß = 0.21, P = 0.016) and change in eGFR (ß = 0.20, P = 0.024) over 3 months (r = 0.35, P = 0.04). CONCLUSIONS: Sitagliptin reduces the ACR through decreasing both blood pressure and eGFR, with no correlation with a decrease in HbA1c over a 3-month period. These results may reflect the direct action of sitagliptin on the kidneys.

Thyroid blood flow as a useful predictor of relapse of Graves' disease after normal delivery in patients with Graves' disease.

OBJECTIVE: Measurement of the peak systolic velocity (PSV) in the inferior thyroid artery (ITA) before withdrawal of an anti-thyroid drug (ATD) is useful for predicting relapse of Graves' disease (GD). We further investigated whether the ITA-PSV can be used for prediction of GD relapse after delivery in euthyroid women with GD who stopped ATD administration during mid- to late pregnancy. PATIENTS AND METHODS: ITA-PSV was monitored monthly for three months after delivery in 42 women with GD aged from 24 to 45 years old (mean+/-SE: 34.7+/-0.92 years old) who met the above criteria. To confirm the stability of the measurement, ITA-PSV was also measured monthly in 32 age-matched non-pregnant normal women and for three months after delivery in 10 age-matched women. RESULTS: ITA-PSV and thyroid volume were higher in women with GD immediately after delivery compared to normal women, but the levels of TSH receptor antibody (TRAb) and thyroid-stimulating antibody (TSAb) did not differ significantly between the two groups. Of the 42 patients, 23 had relapse of GD and the smoker/non-smoker ratio and thyroid volume in these patients immediately after delivery were significantly higher than those in the 19 patients who did not undergo relapse (10/23 vs. 0/19, p<0.0001; 24280.3+/-2280.9 vs. 19670.0+/-2103.7mm(3), p=0.046), while ITA-PSV, TRAb and TSAb did not differ between the two groups of patients. The ITA-PSV ratio was calculated by dividing each value in the follow-up period by that obtained immediately after delivery. A significant increase in the mean ITA-PSV ratio occurred at least one month before the time of relapse (1.00+/-0.00 at -3 months before relapse vs. 1.46+/-0.12 at -1 month, p=0.010; 1.00+/-0.00 at -3 months vs. 1.77+/-0.13 at the time of relapse, p=0.0048). In contrast, there were no significant changes in this ratio during the follow-up period in non-relapse patients. CONCLUSION: Monthly measurement of ITA-PSV after delivery in remitted euthyroid women with GD may assist in early prediction of GD relapse.

Decrease of brachial-ankle pulse wave velocity in female subclinical hypothyroid patients during normalization of thyroid function: a double-blind, placebo-controlled study.

OBJECTIVE: Subclinical hypothyroidism affects 5-15% of the general population, is especially prevalent in females, and may be associated with increased morbidity from cardiovascular disease, although it remains controversial. We recently reported a significant increase in the brachial-ankle pulse wave velocity (baPWV), a parameter of arterial stiffening and an independent predictor of cardiovascular events, in subclinical hypothyroidism without thyroiditis. The current study was performed to assess changes in baPWV in female subclinical hypothyroidism with autoimmune chronic thyroiditis (Hashimoto's disease) after restoration of normal thyroid function. METHODS: In a randomized placebo-controlled study, 95 female subclinical hypothyroid patients were monitored for changes in baPWV before and after levothyroxine (l-T(4)) replacement therapy. Changes in baPWV were also measured in 42 age-matched normal female subjects. RESULTS: The baseline baPWV values in patients with subclinical hypothyroidism were significantly higher than in normal subjects. With attainment of euthyroidism, baPWV showed a significant decrease from 1776.7+/-86.0 to 1674.3+/-79.2 cm/s (P=0.006) in patients treated with l-T(4), but the changes in baPWV and TSH were not correlated. The change in baPWV was significantly and negatively correlated with age and baseline pulse pressure, but multiple regression analysis revealed that these parameters failed to be associated with the change in baPWV. CONCLUSIONS: Sustained normalization of thyroid function during l-T(4) replacement therapy significantly decreases baPWV in female subclinical hypothyroid patients with autoimmune chronic thyroiditis, suggesting the improvement of arterial stiffening and, consequently, possible prevention of cardiovascular disease.

Changes in brachial-ankle pulse wave velocity in subclinical hypothyroidism during normalization of thyroid function.

OBJECTIVE: Subclinical hypothyroidism affects 5-15% of the population and is associated with increased cardiovascular morbidity, although this is controversial. We recently reported a significant increase in brachial-ankle pulse wave velocity (baPWV), a parameter of arterial stiffening and an independent predictor for cardiovascular events, in subclinical hypothyroidism. The current study was performed to assess changes in enhanced baPWV in subclinical hypothyroidism during normalization of thyroid function. METHODS: Forty-two subclinical hypothyroid patients (male/female ratio 8/34) were monitored for changes in baPWV before and after levothyroxine (L-T(4)) replacement therapy. RESULTS: After attaining euthyroidism, 59.5% and 40.5% of the patients showed reduction and increase of baPWV, respectively. Baseline baPWV and pulse pressure were significantly higher in patients with reduced baPWV (1940.3+/-126.4 vs. 1726.4+/-110.4 cm/s, P=0.046; 62.1+/-3.1 vs. 50.7+/-3.7 mmHg, P=0.026, respectively). Baseline baPWV was significantly correlated with baseline pulse pressure in both groups, but the change in baPWV was significantly correlated with baseline pulse pressure only in patients with reduced baPWV (rho=-0.522, P=0.046). The male/female ratio was significantly lower in patients with reduced baPWV (4/21 vs. 7/10), and systolic, diastolic and pulse pressures and pulse rate decreased significantly only in patients with reduced baPWV. CONCLUSIONS: Our results suggest that L-T(4) replacement therapy may be especially beneficial in female subclinical hypothyroid patients with high baseline baPWV and pulse pressure. The beneficial effects of L-T(4) replacement therapy in decreasing arterial stiffening and thus preventing cardiovascular disease might be limited to this sub-population.

Significance of thyroid blood flow as a predictor of methimazole sensitivity in untreated hyperthyroid patients with Graves' disease.

OBJECTIVE: The peak systolic velocity (PSV) of the inferior thyroid artery (ITA) is increased in untreated hyperthyroid patients with Graves' disease (GD). We investigated the clinical significance of the ITA-PSV and its determinants in hyperthyroid GD patients. PATIENTS AND METHODS: ITA-PSV, together with thyroid volume, was measured by ultrasonography in untreated hyperthyroid GD patients (n=49) and healthy subjects (n=22). Established markers of GD activity such as TSH receptor antibody (TRAb), thyroid stimulating antibody (TSAb), vascular endothelial growth factor (VEGF) and immunoglobulin E (IgE) were simultaneously determined. RESULTS: ITA-PSV, thyroid volume, VEGF and IgE were significantly higher in hyperthyroid GD patients than in normal subjects. ITA-PSV in hyperthyroid GD patients was correlated positively with serum levels of FT(3), FT(4) and IgE, smoking index and thyroid volume, and negatively with total, HDL- and LDL-cholesterols, but did not correlate significantly with age, triglyceride, TRAb, TSAb or VEGF. In stepwise regression analysis, ITA-PSV showed significant positive and negative associations with IgE and LDL-cholesterol, respectively, in hyperthyroid GD patients. In the pre-treatment hyperthyroid state, FT(4) and ITA-PSV, but not IgE, were found to be significantly and positively associated with the maintenance dose of methimazole (MMI) required to keep serum TSH within normal range for at least 12 months. CONCLUSION: These results suggest that ITA-PSV in untreated hyperthyroid GD patients may reflect GD activity and thus MMI sensitivity.

Increased levels of C-reactive protein in hypothyroid patients and its correlation with arterial stiffness in the common carotid artery.

OBJECTIVE: Hypothyroidism is associated with increased morbidity from cardiovascular disease. The arterial stiffness index beta (stiffness beta) in the common carotid artery (CCA), which is a parameter of arterial stiffening, is known to increase in hypothyroid patients, while normalization of thyroid function for 1 year by levothyroxine (L-T(4)) replacement therapy significantly decreases CCA stiffness beta. Since serum C-reactive protein (CRP) has recently emerged as an independent factor for cardiovascular risk, the present study was designed to examine whether hypothyroidism causes an increase in CRP and whether the serum CRP level is correlated with CCA stiffness beta in hypothyroid patients. PATIENTS AND METHODS: Serum CRP levels and CCA stiffness beta were determined in 46 patients with hypothyroidism and in 46 age- and sex-matched normal control subjects. Thirty-five patients were further monitored for change in CCA stiffness beta during 1 year in the euthyroid state induced by L-T(4) therapy. RESULTS: Baseline CRP and CCA stiffness beta were both significantly higher in hypothyroid patients than in normal controls [1064.6+/-224.3 vs. 602.1+/-43.3 ng/ml (mean+/-SE), p<0.0001; and 9.25+/-0.84 vs. 8.21+/-0.85, p<0.05, respectively]. Baseline CRP was significantly correlated in a positive manner with baseline values of CCA stiffness beta (r=0.683, p<0.0001). In multivariate analysis, baseline CCA stiffness beta was significantly associated with baseline levels of serum CRP (r=0.740, p<0.0001). During 1 year of L-T(4) replacement therapy, significant decrease in stiffness beta (from 9.25+/-0.84 to 8.57+/-0.58, p<0.0001) to the normal levels was found. Moreover, the change in CCA stiffness beta during L-T(4) replacement therapy was significantly and independently associated in a negative fashion with baseline levels of serum CRP (r=-0.696, p=0.0002). CONCLUSIONS: This study suggests that increased serum CRP might have an important independent role in increased arterial stiffening and the measurement of serum CRP is a useful predictor for the degree of improvement of arterial stiffening in hypothyroid patients.

Central pulse wave velocity is responsible for increased brachial-ankle pulse wave velocity in subclinical hypothyroidism.

OBJECTIVE: Subclinical hypothyroidism affects 5-15% of the general population, and is associated with increased morbidity from cardiovascular disease. We recently reported a significant increase in brachial-ankle pulse wave velocity (baPWV), a parameter of arterial stiffening and an independent predictor for the presence of cardiovascular disease, in subclinical hypothyroidism. The current study was performed to assess which arterial segment is responsible for enhanced baPWV in subclinical hypothyroidism. PATIENTS AND METHODS: Central PWV (PWV in heart-femoral segments), peripheral PWV (PWV in femoral-ankle segments), and baPWV were measured in subclinical hypothyroid patients and normal subjects. RESULTS: Central PWV, baPWV, and peripheral PWV were significantly higher in subclinical hypothyroid patients than in normal subjects. BaPWV was significantly and positively correlated with central and peripheral PWV in both groups. However, a significant and positive correlation between central and peripheral PWV in normal subjects was not found in subclinical hypothyroid patients. Moreover, stepwise regression analysis showed that the association of central PWV with baPWV was stronger than that of peripheral PWV, whereas in normal subjects central PWV was not associated with baPWV. CONCLUSIONS: Our results demonstrate that central and peripheral PWV are significantly higher in subclinical hypothyroid patients, and that the increase in baPWV depends more strongly on central PWV than on peripheral PWV in these patients. This suggests that increased elastic arterial stiffening of the aorta, rather than of peripheral muscular arteries, might be more responsible for increased general arterial stiffening in subclinical hypothyroid patients.

Increased pulse wave velocity in subclinical hypothyroidism.

OBJECTIVE: Subclinical hypothyroidism affects 5-15% of the general population and is associated with increased morbidity from cardiovascular disease. Brachial-ankle pulse wave velocity (baPWV) is a parameter of arterial stiffening and a good independent predictor for the presence of coronary artery disease. This study was performed to assess whether subclinical hypothyroidism might cause enhanced baPWV. PATIENTS AND METHODS: baPWV was examined in subclinical hypothyroid patients (n = 50) and normal control subjects (n = 50). RESULTS: Diastolic blood pressure (DBP), a main risk factor for cardiovascular disease, and baPWV were both significantly higher in subclinical hypothyroid patients than normal subjects. baPWV was significantly positively correlated with age and systolic, diastolic, and pulse pressure and significantly negatively correlated with pulse rate in both subclinical hypothyroid patients and normal subjects. In contrast, there was no significant correlation of baPWV with free T3, free T4, TSH, total, high-density lipoprotein- and low-density lipoprotein-cholesterol, and the preejection time to ejection time ratio. A comparison of individual values of baPWV and DBP and regression slopes in two groups revealed that baPWV values increase to a larger extent than the increase in DBP in subclinical hypothyroid patients. In both groups, stepwise regression analysis showed a significant and independent association of DBP with baPWV. CONCLUSIONS: The present study demonstrated significant increases of baPWV and DBP in subclinical hypothyroid patients. Furthermore, the results suggest that increased DBP might be one of the main factors responsible for increased arterial stiffening in subclinical hypothyroid patients.

The significance of thyroid blood flow at the inferior thyroid artery as a predictor for early Graves' disease relapse.

OBJECTIVE: We investigated the clinical usefulness of thyroid blood-flow measurement in predicting relapse of Graves' disease (GD) in comparison with known risk factors for GD relapse. MEASUREMENT: Thyroid blood flow was measured in pulsed Doppler mode at the inferior thyroid artery (ITA), and the peak systolic velocity (PSV) calculated. PATIENTS: ITA-PSV was measured in euthyroid GD patients (n = 79) immediately before withdrawal of anti-thyroid drug (ATD) and in healthy subjects (n = 17). RESULTS: In the 79 euthyroid GD patients, the values of free triiodothyronine (FT3), TSH receptor autoantibody (TRAb), ITA-PSV and thyroid volume were significantly higher in the relapse group (n = 40) than in the nonrelapse group (n = 39) and the Youden index of ITA-PSV was significantly higher than that of FT3, TSH, TRAb and vascular endothelial growth factor (VEGF). CONCLUSION: ITA-PSV may assist in the prediction of early GD relapse after ATD withdrawal.

Plasma levels of adiponectin and soluble thrombomodulin in hypothyroid patients with normal thyroid function following levothyroxine replacement therapy.

Hypothyroidism is associated with increased morbidity from cardiovascular disease, and adiponectin (ApN) is a newly-identified adipocytokine, which is expressed in human adipose cells and may have a protective effect against the development of coronary artery disease. The aim of the study was to evaluate the involvement of ApN secretion in hypothyroid patients with normal thyroid function following levothyroxine (L-T(4)) replacement therapy, and to associate plasma ApN levels with intima-media thickness (IMT) in the common carotid artery (CCA), an indicator of early atherosclerosis, and cardiovascular parameters including soluble thrombomodulin (sTM), a plasma endothelial injury marker. The CCA IMT and plasma levels of ApN and sTM were measured in 52 hypothyroid patients and in age-, sex- and body mass index (BMI)-matched normal control subjects. Thirty-six of the hypothyroid patients were further monitored for changes in these markers during 1 year in a euthyroid state induced by L-T(4) replacement therapy. Although the basal CCA IMT was significantly higher in hypothyroid patients [0.633 +/- 0.018 mm (mean +/- S.E.)] than in control subjects (0.552 +/- 0.022 mm, P < 0.005), both groups had similar baseline ApN and sTM levels [10.23 +/- 0.76 vs. 10.10 +/- 0.93 microg/ml: NS; and 2.58 +/- 0.14 vs. 2.68 +/- 0.20 ng/ml: NS, respectively]. Simple regression analysis revealed that plasma ApN was significantly correlated in a positive manner with age (r = 0.339, P = 0.015), HDL-cholesterol (r = 0.295, P = 0.048), and sTM (r = 0.490, P = 0.0005), but not with CCA IMT (r = 0.059, P = 0.742). In multivariate analysis, the plasma ApN level was significantly associated with that of sTM (r = 0.546, P = 0.0001) and with serum high-density lipoprotein (HDL)-cholesterol levels (r = 0.291, P = 0.029) in hypothyroid patients. During 1 year of L-T(4) replacement therapy, hypothyroid patients showed a significant decrease in CCA IMT, to 0.553 +/- 0.016 mm (P < 0.0001), a level comparable to normal controls, but no significant change in ApN (from 10.79 +/- 1.07 to 10.6 9+/- 1.14 microg/ml, NS) or sTM (from 2.59 +/- 0.15 to 2.74 +/- 0.18 ng/ml, NS). Hence, we provide evidence that ApN and sTM might not contribute to enhanced atherosclerosis, as reflected by increased CCA IMT in hypothyroid patients. However, this is the first report to demonstrate a positive and significant association of sTM with ApN. These data support the hypothesis that sTM is one of the determinant of ApN and thus suggest the presence of an sTM-associated regulatory mechanism for ApN secretion in hypothyroid patients.

Increased levels of serum osteoprotegerin in hypothyroid patients and its normalization with restoration of normal thyroid function.

Hypothyroidism is associated with increased morbidity from cardiovascular disease, and an increase in serum osteoprotegerin (OPG) has recently been reported to be associated with the severity of coronary heart disease and cardiovascular mortality. The present study was designed to examine whether hypothyroidism causes an increase in serum OPG, and to determine whether levothyroxine (L-T4) replacement therapy might suppress serum OPG levels in hypothyroid patients. Fifty-three hypothyroid patients with chronic thyroiditis and age- and sex-matched normal control subjects were examined for the levels of serum OPG and plasma von Willebrand factor (vWF), a vascular injury marker. Thirty-seven of the hypothyroid patients were further monitored for changes in these markers during 1 year in a euthyroid state induced by L-T4 replacement therapy. Baseline OPG was significantly higher in hypothyroid patients than in normal controls (4.51 +/- 0.50 vs 3.72 +/- 0.23 pmol/l (mean +/- S.E.); P = 0.0182). In multivariate analysis, baseline OPG was significantly associated with baseline levels of TSH (r = 0.280, P = 0.0162) and vWF (r = 0.626, P < 0.0001). During one year of L-T4 replacement therapy, hypothyroid patients showed a significant decrease in OPG levels from 4.35 +/- 0.51 to 3.48 +/- 0.26 pmol/l (P = 0.0166), a level comparable to normal controls. The change in serum OPG levels during L-T4 replacement therapy was significantly and independently associated in a negative fashion with baseline vWF (r = -0.503, P = 0.0014). This study suggested that the severity of hypothyroidism and vascular injury might have important independent roles in increasing the serum OPG level in hypothyroid patients. Furthermore, it was demonstrated that a sustained euthyroid state might have the potential to decrease the serum OPG level in hypothyroid patients and that the degree of vascular injury in the hypothyroid state is independently associated with a decrease in serum OPG during a 1-year normalization of thyroid function.

Decrease of arterial stiffness at common carotid artery in hypothyroid patients by normalization of thyroid function.

This study examined the effect of hypothyroidism on arterial stiffening and the effect of levothyroxine (l-T(4)) replacement. The arterial stiffness index beta (stiffness beta) and intima-media thickness (IMT), a parameter of arterial stiffening and thickening, respectively, were determined in common carotid artery (CCA) by ultrasonography in 30 hypothyroid patients before and after 1 year of normalization of thyroid function by l-T(4) replacement. Baseline CCA stiffness beta and IMT was significantly higher in the hypothyroid patients than in age- and sex-matched normal controls [9.46 +/- 0.93 vs. 8.02 +/- 0.91 (mean +/- SE); P < 0.05, 0.635 +/- 0.018 mm vs. 0.541 +/- 0.019 mm; P < 0.005, respectively]. In multivariate analysis, baseline stiffness beta was significantly associated with baseline levels of IMT (r = 0.457, P = 0.0311), FT(4) (r = -0.413, P = 0.0169), and a plasma vascular injury marker, von Willebrand factor (vWF) (r = 0.412, P = 0.0261). During 1 year of euthyroidism, 22 and 29 out of 30 patients showed significant decreases of stiffness beta and IMT to normal respective level, from 9.46 +/- 0.93 to 7.58 +/- 0.34 and from 0.635 +/- 0.018 to 0.552 +/- 0.015 mm, respectively. Change in stiffness beta during l-T(4) therapy correlated significantly in a negative manner with baseline levels of age (r = -0.465, P = 0.011) and IMT (r = -0.406, P = 0.029). Stiffness beta after but not before l-T(4) therapy showed a tendency towards a positive correlation with age. This study suggested that increases of arterial thickening, and plasma vWF, and a reduction in serum FT(4) might have an important role independently in the increased arterial stiffening in hypothyroid patients. Furthermore, it was demonstrated that sustained euthyroidism might have the potential to reverse arterial stiffening in addition to thickening in hypothyroid patients.