Sodium glucose cotransporter-2 inhibitors and heart disease: Current perspectives.

Sodium glucose cotransporter-2 inhibitors (SGLT-2i) are antidiabetic medications with remarkable cardiovascular (CV) benefits proven by multiple randomised controlled trials and real-world data. These drugs are also useful in the prevention of CV disease (CVD) in patients with diabetes mellitus (DM). Although DM as such is a huge risk factor for CVD, the CV benefits of SGLT-2i are not just because of antidiabetic effects. These molecules have proven beneficial roles in prevention and management of nondiabetic CVD and renal disease as well. There are various molecular mechanisms for the organ protective effects of SGLT-2i which are still being elucidated. Proper understanding of the role of SGLT-2i in prevention and management of CVD is important not only for the cardiologists but also for other specialists caring for various illnesses which can directly or indirectly impact care of heart diseases. This clinical review compiles the current evidence on the rational use of SGLT-2i in clinical practice.

SHOX Variations in Idiopathic Short Stature in North India and a Review of Cases from Asian Countries

Objective: Short stature homeobox (SHOX) haploinsufficiency underlies idiopathic short stature (ISS) and Leri-Weill dyschondrosteosis. The worldwide prevalence of SHOX variations in ISS varies from 2.5% to 15.0%. The aim of this study was to assess the implication of SHOX variation in ISS in North Indians and compare this with other cases of SHOX variations from Asian population. Methods: SHOX gene analysis was carried out by multiplex ligation-dependent probe amplification followed by Sanger sequencing in 54 patients with variable phenotypes. Comparison with other reports in a meta-analysis comprising the current study and 11 previous studies (n=979) was performed. Results: SHOX analysis resulted in 12.9% positivity (7.4% deletions and 5.5% duplications). SHOX association was seen significantly related to gender, with predominance in females (p=0.047). Short arms and forearms were the only significantly associated trait seen in 51.9% of children. The overall prevalence of SHOX variation was 15.2% in Asians with ISS. No significant difference was found in geographical region-specific analysis. Conclusion: This study summarises findings from the last decade and provides an updated picture of the prevalence of SHOX variations in Asians, emphasizing their potential as therapeutic targets in ISS patients. Further high quality, large investigations including functional validation is warranted to validate this association.

Critical review of bone health, fracture risk and management of bone fragility in diabetes mellitus.

The risk of fracture is increased in both type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM). However, in contrast to the former, patients with T2DM usually possess higher bone mineral density. Thus, there is a considerable difference in the pathophysiological basis of poor bone health between the two types of diabetes. Impaired bone strength due to poor bone microarchitecture and low bone turnover along with increased risk of fall are among the major factors behind elevated fracture risk. Moreover, some antidiabetic medications further enhance the fragility of the bone. On the other hand, antiosteoporosis medications can affect the glucose homeostasis in these patients. It is also difficult to predict the fracture risk in these patients because conventional tools such as bone mineral density and Fracture Risk Assessment Tool score assessment can underestimate the risk. Evidence-based recommendations for risk evaluation and management of poor bone health in diabetes are sparse in the literature. With the advancement in imaging technology, newer modalities are available to evaluate the bone quality and risk assessment in patients with diabetes. The purpose of this review is to explore the pathophysiology behind poor bone health in diabetic patients. Approach to the fracture risk evaluation in both T1DM and T2DM as well as the pragmatic use and efficacy of the available treatment options have been discussed in depth.

Total T4 rise in pregnancy: a relook?

BACKGROUND: Total T4 (TT4) measurement is preferred to free T4 (FT4) especially in last part of pregnancy. Guidelines by American Thyroid Association, European Thyroid Association and Endocrine Society state that TT4 increases 1.5 times pre-pregnant levels after week 16 of pregnancy. However, this is based on a small study conducted 40 years ago which used radioimmunoassay for determination in changes in TT4. MATERIALS AND METHODS: A cross-sectional study was undertaken to find reference interval for thyroid function in different trimester of pregnancy with special reference to look at the degree of elevation of TT4 as compared to non-pregnant women. Two hundred non-pregnant women (excluding oral contraceptive users) and 600 pregnant women (200 from each trimester) aged 18-40 years were consecutively recruited starting from around 6th week of pregnancy having confirmed singleton pregnancy diagnosed at 8th week by ultrasound. The exclusion criteria included: (1) a personal or family history of thyroid disease; (2) presence of goiter or nodule confirmed by ultrasound; (3) anti-TPO antibody positive state (titre > 35 IU/ml). All subjects were tested for urinary spot iodine concentration and those with UIC < 150 µg/L were excluded. Finally, thyroid function tests (TSH, FT4, TT4, TT3) of 168 non-pregnant women and 163, 153 and 148 women at 1st, 2nd and 3rd trimester respectively were analysed.. RESULTS: Total T4 (mean ± SD, µg/dl) in non pregnant women and in different trimesters was 8.95 ± 1.71, 9.71 ± 2.39, 12.11 ± 1.55, 11.83 ± 1.49 respectively. Rise in TT4 occurred between 10-18th week. The mean TT4 in second trimester increased by 25% as compared with the value at 6-9th week and by 35% as compared to non-pregnant value. CONCLUSION: Rise in total T4 in second trimester pregnancy is only around 25% as compared to first trimester value and 35% than the non-pregnant value. Hence multiplying non-pregnant T4 value by 1.5 may actually over-diagnose maternal hypothroxinemia and lead to inappropriate diagnosis and treatment of isolated maternal hypothyroxinemia in a significant proportion of subjects.

Levothyroxine Absorption Test to Differentiate Pseudomalabsorption from True Malabsorption.

BACKGROUND: The levothyroxine absorption test for evaluation of pseudomalabsorption in patients with primary hypothyroid is not standardised. An individual in whom a workup for malabsorption is warranted remains undefined. METHODS: Twenty-five euthyroid, 25 newly diagnosed hypothyroid, 25 treated hypothyroid with normalised TSH, and 25 hypothyroid subjects with elevated TSH despite adequate dose of levothyroxine for more than 6 months, and 10 euthyroid subjects with true malabsorption were administered levothyroxine (10 µg/kg or maximum 600 µg) to study its absorption profile by measuring free T4 level at hourly intervals for 5 h. Results : Free T4 peaked at 3 h with marginal insignificant decline at 4 h in all groups. The increments of free T4 (between baseline and 3 h) of the four groups (except malabsorption) were not statistically different. The mean increment of free T4 in true malabsorption was 0.39 ng/dL (95% CI: 0.29-0.52) and it was 0.78 ng/dL (95% CI: 0.73-0.85) (10.4 pmol/L) for other groups combined together. The cut off of free T4 increment at 3 h from baseline above 0.40 ng/dL had a sensitivity of 97% and specificity of 80% (AUC 0.904, p < 0.001) to exclude true malabsorption. CONCLUSION: Subjects with elevated TSH on adequate dose of LT4 can be reliably diagnosed to be non-adherent to treatment with levothyroxine absorption test. The incremental value above 0.40 ng/dL (5.14 pmol/L) at 3 h may be useful to identify individuals where workup of malabsorption is unwarranted.

Thyroid Status in Patients with Type 2 Diabetes Attending a Tertiary Care Hospital in Eastern India.

OBJECTIVE: Type 2 diabetes mellitus and thyroid dysfunction (TD) are two major public health endocrine problem, but the prevalence of TD and iodine status in patients with T2 DM in India is less studied. The study objective was to explore the prevalence of TD and to evaluate iodine health in type 2 diabetes patients attending a tertiary care center in Eastern India. METHODS: Consecutive 100 patients with diabetes attending outpatient department were evaluated clinically and biochemically (thyrotropin [TSH], free thyroxine, anti-TPO antibody, and urinary iodine). We excluded pregnant women or patients taking drugs that can alter thyroid function. Subclinical hypothyroid and overt hypothyroidism were diagnosed as per standard definitions. RESULTS: Out of 100 patients were analyzed, 51 (51%) were male. Mean (±standard deviation) age was 45.4 ± 11.2 years, body mass index 24.1 ± 4.28 kg/m2, and duration of diabetes 7.76 ± 5.77 years. The prevalence of subclinical hypothyroidism and overt hypothyroidism was 23/100 (23%) and 3/100 (3%), respectively. Thyroid autoantibody was positive in 13 (13.1%) patients. All patients were iodine sufficient. A trend toward increased neuropathy (r = 0.45) and nephropathy (r = -0.29) was associated with rising TSH. CONCLUSION: Almost one in four people living with diabetes are suffering from TD. Thus, routine screening should be implemented. Salt iodination program is a huge success in this part of the country.

Parathyroid Carcinoma and Persistent Hypercalcemia: A Case Report and Review of Therapeutic Options.

Parathyroid carcinomas are very uncommon, accounting for 0.1% to 5% of all causes of primary hyperparathyroidism. Parathyroid-jaw tumor syndrome, with a mutation in HRPT2 that encodes parafibromin, is the most common genetic association. Unique features include aggressive clinical course and a lack of preoperative definitive diagnostic criteria. The authors report a case of a 33-year-old male with bilateral nephrocalcinosis, a left-sided neck mass, high calcium, very high parathormone level and a history of parathyroid adenectomy. Computed tomography and 99m-technetium methoxyisobutylisonitrile scan revealed a localized tumor in the left inferior parathyroid region. The patient underwent radical surgery, and histopathology revealed characteristic features of parathyroid carcinoma. Preoperative identification with clinical clues is very important to plan a more radical surgical approach, as both radiotherapy and chemotherapy are ineffective. Recurrence is common and mostly occurs within 2-3 years after surgery. Patient's age, histology and tumor DNA aneuploidy are predictors of survival. Hypercalcemia is controlled with calcimimetics, bisphosphonates and denosumab in inoperable cases. Furthermore, biologic therapy with parafibromin and telomerase inhibitors is under development.

Lesson of the month 2: Houssay phenomenon - hypopitutarism leading to remission of diabetes.

Because of a pituitary insult and the subsequent loss of counter-regulatory hormones, individuals can experience increased sensitivity to insulin, hypoglycaemia or even complete amelioration of diabetes; this is known as the Houssay phenomenon. Severe dehydration following diarrhoea can lead to pituitary infarction causing hypopituitarism. We describe this situation in a patient with insulin-treated type-2 diabetes presenting with recurrent hypoglycaemia and cessation of insulin requirement along with weight loss, hypotension and hyponatraemia. Pituitary imaging revealed a partial empty sella and a synacthen stimulation test revealed an initial positive response but later loss of response, proving recent-onset pituitary dysfunction. Physicians should keep this possibility in mind while treating hypoglycaemia in stable diabetic individuals. Judicious supplementation of deficient hormones is of utmost importance.