Physiological changes in pregnancy and their influence on the endocrine investigation.

BACKGROUND: Physiological changes in pregnancy may result in significant alterations in endocrine hormone profiles, serum and urine electrolytes and endocrine gland morphology on imaging. Pregnancy-specific pathophysiological processes may also affect the results for endocrine tests. Investigation of endocrine disorders in pregnancy requires knowledge of these changes and awareness of the safety of dynamic hormone testing and imaging for the mother and foetus. OBJECTIVE: This review seeks to outline the important physiological changes in pregnancy affecting reference intervals of basal and dynamic endocrine tests in pregnancy and the scenarios in which these changes are clinically significant, the pregnancy-specific disorders that may affect the investigation of endocrine disorders, and the safety of dynamic testing and imaging. CONCLUSION: Awareness of the effect of physiological changes, and the potential impact of pregnancy-specific disorders of endocrine tests, and the safety of imaging is crucial to the management of endocrine disorders in pregnancy.

Continuous Glucose Monitoring in Young Adults With Type 1 Diabetes: Impact on Hypoglycemia Confidence and Fear.

Background: Fear of hypoglycemia in people with type 1 diabetes has a detrimental effect on glycemic control and quality of life. The association between continuous glucose monitoring (CGM) and hypoglycemia confidence and fear has not previously been assessed in the young adult population. Methods: This was a prospective cohort study using questionnaires to assess the impact of CGM on hypoglycemia confidence (using the Hypoglycemia Confidence Scale [HCS]) and hypoglycemia fear (using the Hypoglycemia Fear Survey II [HFS]) in 40 young adults with a preexisting diagnosis of type 1 diabetes. Results: Scores on the HCS were greater at baseline for those with a longer duration of diabetes. Participants with higher general anxiety scores on the Generalized Anxiety Disorder 7-item scale had higher hypoglycemia fear at baseline (total score and worry component, but not behavior component of the HFS). Between baseline and follow-up, HCS scores increased on average by 0.2 (95% CI 0.1-0.4, P = 0.01) on a scale of 1-4. HFS scores decreased by 1.8 (95% CI -3.0 to -0.5, P = 0.006) on a scale of 0-24 for the worry component and by 2.5 (95% CI -4.4 to -0.6, P = 0.01) on a scale of 0-44 for total (worry + behavior components). At follow up, 83% of participants planned to continue using CGM all or most of the time. There was a very high self-reported effect of CGM on life with diabetes (median 8.0 [interquartile range 6.5-10.0], where 10 indicated a very big difference). Conclusion: Hypoglycemia confidence and fear improve with CGM use in young adults.

Hyperdynamic Right Heart Function in Graves' Hyperthyroidism Measured by Echocardiography Normalises on Restoration of Euthyroidism.

BACKGROUND: Graves' hyperthyroidism commonly causes tachycardia and may result in pulmonary hypertension and high output cardiac failure. There is limited information regarding the effect of treatment on cardiac function measured using modern echocardiographic techniques. METHODS: Eight individuals with Graves' hyperthyroidism, aged 22-64 years, underwent comprehensive transthoracic echocardiography at three time points: before treatment, two weeks after commencement of carbimazole, and at six months or more when euthyroid. Exercise capacity was assessed using the 6-minute-walk-distance (6MWT), and quality of life was assessed by Medical Outcome Study 36-item Short-Form Health Status Survey. RESULTS: All individuals were rendered euthyroid by final assessment. At presentation, there was evidence of hyperdynamic right ventricular function as measured by peak systolic velocity of the free wall of the tricuspid annulus, tricuspid annular plane systolic excursion and right ventricular ejection fraction, which normalised after resolution of thyrotoxicosis. Baseline heart rate correlated significantly with severity of the thyrotoxicosis for either free T4 (r = 0.91, p=0.01) or free T3 (r=0.94, p=0.001). No individual had measurable pulmonary hypertension. Cardiac output was significantly lower in the euthyroid compared to the thyrotoxic state (p=0.03). A higher baseline TSH-receptor antibody titre corresponded to a greater improvement in exercise capacity (r=0.76, p<0.05) and physical quality of life (r=0.73, p<0.05) on resolution of the hyperthyroidism. CONCLUSION: Graves' hyperthyroidism causes increased cardiac output and a hyperdynamic right ventricle which normalise on restoration of the euthyroid state.

Advanced glycation end products as predictors of renal function in youth with type 1 diabetes.

To examine if skin autofluorescence (sAF) differed in early adulthood between individuals with type 1 diabetes and age-matched controls and to ascertain if sAF aligned with risk for kidney disease. Young adults with type 1 diabetes (N = 100; 20.0 ± 2.8 years; M:F 54:46; FBG-11.6 ± 4.9 mmol/mol; diabetes duration 10.7 ± 5.2 years; BMI 24.5(5.3) kg/m2) and healthy controls (N = 299; 20.3 ± 1.8 years; M:F-83:116; FBG 5.2 ± 0.8 mmol/L; BMI 22.5(3.3) kg/m2) were recruited. Skin autofluorescence (sAF) and circulating AGEs were measured. In a subset of both groups, kidney function was estimated by GFRCKD-EPI CysC and uACR, and DKD risk defined by uACR tertiles. Youth with type 1 diabetes had higher sAF and BMI, and were taller than controls. For sAF, 13.6% of variance was explained by diabetes duration, height and BMI (Pmodel = 1.5 × 10-12). In the sub-set examining kidney function, eGFR and sAF were higher in type 1 diabetes versus controls. eGFR and sAF predicted 24.5% of variance in DKD risk (Pmodel = 2.2 × 10-9), which increased with diabetes duration (51%; Pmodel < 2.2 × 10-16) and random blood glucose concentrations (56%; Pmodel < 2.2 × 10-16). HbA1C and circulating fructosamine albumin were higher in individuals with type 1 diabetes at high versus low DKD risk. eGFR was independently associated with DKD risk in all models. Higher eGFR and longer diabetes duration are associated with DKD risk in youth with type 1 diabetes. sAF, circulating AGEs, and urinary AGEs were not independent predictors of DKD risk. Changes in eGFR should be monitored early, in addition to uACR, for determining DKD risk in type 1 diabetes.

T-Cell Expression and Release of Kidney Injury Molecule-1 in Response to Glucose Variations Initiates Kidney Injury in Early Diabetes.

Half of the mortality in diabetes is seen in individuals <50 years of age and commonly predicted by the early onset of diabetic kidney disease (DKD). In type 1 diabetes, increased urinary albumin-to-creatinine ratio (uACR) during adolescence defines this risk, but the pathological factors responsible remain unknown. We postulated that early in diabetes, glucose variations contribute to kidney injury molecule-1 (KIM-1) release from circulating T cells, elevating uACR and DKD risk. DKD risk was assigned in youth with type 1 diabetes (n = 100; 20.0 ± 2.8 years; males/females, 54:46; HbA1c 66.1 [12.3] mmol/mol; diabetes duration 10.7 ± 5.2 years; and BMI 24.5 [5.3] kg/m2) and 10-year historical uACR, HbA1c, and random blood glucose concentrations collected retrospectively. Glucose fluctuations in the absence of diabetes were also compared with streptozotocin diabetes in apolipoprotein E -/- mice. Kidney biopsies were used to examine infiltration of KIM-1-expressing T cells in DKD and compared with other chronic kidney disease. Individuals at high risk for DKD had persistent elevations in uACR defined by area under the curve (AUC; uACRAUC0-10yrs, 29.7 ± 8.8 vs. 4.5 ± 0.5; P < 0.01 vs. low risk) and early kidney dysfunction, including ∼8.3 mL/min/1.73 m2 higher estimated glomerular filtration rates (modified Schwartz equation; Padj < 0.031 vs. low risk) and plasma KIM-1 concentrations (∼15% higher vs. low risk; P < 0.034). High-risk individuals had greater glycemic variability and increased peripheral blood T-cell KIM-1 expression, particularly on CD8+ T cells. These findings were confirmed in a murine model of glycemic variability both in the presence and absence of diabetes. KIM-1+ T cells were also infiltrating kidney biopsies from individuals with DKD. Healthy primary human proximal tubule epithelial cells exposed to plasma from high-risk youth with diabetes showed elevated collagen IV and sodium-glucose cotransporter 2 expression, alleviated with KIM-1 blockade. Taken together, these studies suggest that glycemic variations confer risk for DKD in diabetes via increased CD8+ T-cell production of KIM-1.

Changes in biochemical tests in pregnancy and their clinical significance.

Interpretation of laboratory investigations relies on reference intervals. Physiological changes in pregnancy may result in significant changes in normal values for many biochemical assays, and as such results may be misinterpreted as abnormal or mask a pathological state. The aims of this review are as follows: 1. To review the major physiological changes in biochemical tests in normal pregnancy. 2. To outline where these physiological changes are important in interpreting laboratory investigations in pregnancy. 3. To document the most common causes of abnormalities in biochemical tests in pregnancy, as well as important pregnancy-specific causes.

Review article: Investigations and the pregnant woman in the emergency department - part 2: Point-of-care ultrasound, electrocardiography, respiratory function tests and radiology.

Accurate assessment of the pregnant patient in the ED depends on knowledge of physiological changes in pregnancy, and how these changes may impact on pathology tests, appearance on point-of-care ultrasound, electrocardiography and respiratory function tests. In addition, the emergency physician needs to be cognisant of disorders that are unique to or more common during pregnancy. Part 2 of this review addresses the role of point-of-care ultrasound in pregnancy, physiological changes that may affect interpretation of point-of-care ultrasound, changes in electrocardiography and respiratory function tests, and the safety of radiological procedures in the pregnant patient. Part 1 addressed potential deviations in laboratory investigation reference intervals resulting from physiological alterations in pregnancy and the important causes of abnormal laboratory results in pregnancy.

Review article: Investigations and the pregnant woman in the emergency department - part 1: Laboratory investigations.

Accurate assessment of the pregnant patient in the ED depends on knowledge of physiological changes in pregnancy, and how these changes may impact on pathology tests, appearance on point-of-care ultrasound and electrocardiography. In addition the emergency physician needs to be cognisant of disorders that are unique to or more common in pregnancy. Part 1 of this review addresses potential deviations in laboratory investigation reference intervals resulting from physiological alterations in pregnancy, and the important causes of abnormal laboratory results in pregnancy. Part 2 will address the role of point-of-care ultrasound in pregnancy, physiological changes that may affect interpretation of point-of-care ultrasound, physiological changes in electrocardiography, and the safety of radiological procedures in the pregnant patient.

Adrenarche unmasks compound heterozygous 3ß-hydroxysteroid dehydrogenase deficiency: c.244G>A (p.Ala82Thr) and the novel 931C>T (p.Gln311*) variant in a non-salt wasting, severely undervirilised 46XY.

3ß-Hydroxysteroid dehydrogenase type II deficiency (3ßHSD2) congenital adrenal hyperplasia is a rare cause of ambiguous genitalia, resulting in abnormal virilisation in both 46XY and 46XX. We describe a case of 46XY ambiguous genitalia that was misdiagnosed as androgen insensitivity syndrome. The correct diagnosis was made after adrenarche. Genotyping demonstrated compound heterozygosity in two alleles, the previously described c.244G>A (p.Ala82Thr), and a novel 931C>T(p.Gln311*) variant. We suggest that adrenarche unmasked the condition by driving cortisol production to rates that caused the mutant 3bHSD2 enzyme to become rate limiting for cortisol production. This case illustrates how markedly different the effects of this condition may be on androgen production compared with glucocorticoid and mineralocorticoid production. It also demonstrates how current guidelines based on urinary steroids and cortisol sufficiency may not arrive at the correct diagnosis, and underlines the importance of gene testing in the work-up of disorders of sexual differentiation.

Neurofibromatosis-related phaeochromocytoma: two cases with large tumours and elevated plasma methoxytyramine.

UNLABELLED: We present two cases of adrenal phaeochromocytoma in patients with a previous diagnosis of neurofibromatosis type 1 (NF1). One had an adrenergic phenotype. The other had a more noradrenergic phenotype. Both had large primary tumours, which increases the likelihood of malignancy. Both also had elevated plasma-free methoxytyramine, which has been linked with malignancy even in non-SDHB phaeochromocytomas. LEARNING POINTS: Phaeochromocytoma can have varied clinical presentations.Methoxytyramine can be useful in the biochemical work-up of both SDHB-positive and SDHB-negative phaeochromocytoma.The utility of methoxytyramine as a marker of malignancy in NF1-related phaeochromocytoma is unclear, and cases with elevated titres warrant longer follow-up.

Recurrent pituitary apoplexy due to two successive neoplasms presenting with ocular paresis and epistaxis.

UNLABELLED: A case of recurrent pituitary apoplexy is described in a 72-year-old man who initially presented with haemorrhage in a non-functioning pituitary adenoma. Five years later, he re-presented with a severe pituitary haemorrhage in an enlarging sellar mass invading both cavernous sinuses causing epistaxis and bilateral ocular paresis. Subsequent histology was consistent with a sellar malignant spindle and round cell neoplasm. Multiple pituitary tumours have previously been reported to coexist in the same individual, but to our knowledge this is the only case where two pathologically distinct pituitary neoplasms have sequentially arisen in a single patient. This case is also notable with respect to the progressive ocular paresis, including bilateral abducens nerve palsies, and the presentation with epistaxis. LEARNING POINTS: Ocular paresis in pituitary apoplexy can result from tumour infiltration of nerves, or by indirect compression via increased intrasellar pressure.Epistaxis is a very rare presentation of a pituitary lesion.Epistaxis more commonly occurs following trans-sphenoidal surgery, and can be delayed.