Search

Starvation ketoacidosis (SKA) is a rarer cause of ketoacidosis. Most patients will only have a mild acidosis, but if exacerbated by stress can result in a severe acidosis. We describe a 66-year-old man admitted with reduced consciousness and found to have a severe metabolic acidosis with raised anion gap. His body mass index (BMI) was noted to be within the healthy range at 23 kg/m2; however, it was last documented 1 year previously at 28 kg/m2 with no clear timeframe of weight loss. While his acidosis improved with intravenous fluids, he subsequently developed severe electrolyte imbalance consistent with refeeding during his admission. Awareness of SKA as a cause for high anion gap metabolic acidosis is important and knowledge of management including intravenous fluids, thiamine, dietetic input and electrolyte replacement is vital.

Premature cardiovascular disease and death with a functioning graft are leading causes of death and graft loss, respectively, in kidney transplant recipients (KTRs). Vascular stiffness and calcification are markers of cardiovascular disease that are prevalent in KTR and associated with subclinical vitamin K deficiency. We performed a single-center, phase II, parallel-group, randomized, double-blind, placebo-controlled trial (ISRCTN22012044) to test whether vitamin K supplementation reduced vascular stiffness (MRI-based aortic distensibility) or calcification (coronary artery calcium score on computed tomography) in KTR over 1 year of treatment. The primary outcome was between-group difference in vascular stiffness (ascending aortic distensibility). KTRs were recruited between September 2017 and June 2018, and randomized 1:1 to vitamin K (menadiol diphosphate 5 mg; n = 45) or placebo (n = 45) thrice weekly. Baseline demographics, clinical history, and immunosuppression regimens were similar between groups. There was no impact of vitamin K on vascular stiffness (treatment effect -0.23 [95% CI -0.75 to 0.29] × 10-3 mmHg-1 ; p = .377), vascular calcification (treatment effect -141 [95% CI - 320 to 38] units; p = .124), nor any other outcome measure. In this heterogeneous cohort of prevalent KTR, vitamin K supplementation did not reduce vascular stiffness or calcification over 1 year. Improving vascular health in KTR is likely to require a multifaceted approach.

BACKGROUND: Vascular calcification, a risk factor for cardiovascular disease, is common among patients with CKD and is an independent contributor to increased vascular stiffness and vascular risk in this patient group. Vitamin K is a cofactor for proteins involved in prevention of vascular calcification. Whether or not vitamin K supplementation could improve arterial stiffness in patients with CKD is unknown. METHODS: To determine if vitamin K supplementation might improve arterial stiffness in patients in CKD, we conducted a parallel-group, double-blind, randomized trial in participants aged 18 or older with CKD stage 3b or 4 (eGFR 15–45 ml/min per 1.73 m(2)). We randomly assigned participants to receive 400 μg oral vitamin K2 or matching placebo once daily for a year. The primary outcome was the adjusted between-group difference in carotid-femoral pulse wave velocity at 12 months. Secondary outcomes included augmentation index, abdominal aortic calcification, BP, physical function, and blood markers of mineral metabolism and vascular health. We also updated a recently published meta-analysis of trials to include the findings of this study. RESULTS: We included 159 randomized participants in the modified intention-to-treat analysis, with 80 allocated to receive vitamin K and 79 to receive placebo. Mean age was 66 years, 62 (39%) were female, and 87 (55%) had CKD stage 4. We found no differences in pulse wave velocity at 12 months, augmentation index at 12 months, BP, B-type natriuretic peptide, or physical function. The updated meta-analysis showed no effect of vitamin K supplementation on vascular stiffness or vascular calcification measures. CONCLUSIONS: Vitamin K2 supplementation did not improve vascular stiffness or other measures of vascular health in this trial involving individuals with CKD. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Vitamin K therapy to improve vascular health in patients with chronic kidney disease, ISRCTN21444964 (www.isrctn.com)

Raised total cholesterol (TC) and reduced high-density lipoprotein (HDL) cholesterol levels are established cardiovascular disease (CVD) risk factors. However, in autoimmune conditions the lipid-CVD association appears paradoxical, with inflammation as a potential confounding factor. We therefore sought to model the relationship between systemic inflammatory illness and lipid levels using C-reactive protein (CRP) as the prototypical marker of inflammation. Our hypothesis was that there would be an inverse association between raised CRP levels and both TC and HDL-cholesterol levels.Results from samples analysed simultaneously for CRP and lipids in a 6-month period were collected retrospectively from a large city hospital laboratory database that collates results from both primary and secondary care. The relationships between CRP and lipids were determined using graphical techniques and empirical, non-parametric, best fit models.A total of 11 437 blood samples was included. We identified a significant (p0.001) biphasic relationship between TC and CRP: TC increased within the healthy CRP range of less than 5 mg/l, but decreased with CRP levels above 10 mg/l. The two effects approximately cancelled each other out in the intermediate CRP range of 5-10 mg/l. There was an inverse relationship between HDL-cholesterol and CRP.Lipid levels change significantly during inflammatory illness in a population with both acute and chronic conditions. These results provide a strong epidemiological basis for the better understanding of lipid changes in inflammatory conditions and with anti-inflammatory therapies.

Genetic variation of the glucocorticoid receptor (GR) locus is associated with differences in blood pressure. To define the intermediate phenotypes associated with this variation, we investigated the biochemical and clinical significance of a BclI restriction fragment length polymorphism of the GR locus in 64 normal male volunteers. Blood samples were genotyped as either AA (homozygous large allele; n = 6), Aa (heterozygous; n = 51), or aa (homozygous small allele, n = 7). Four primary glucocorticoid variables were measured including GR binding characteristics and glucocorticoid-sensitive lysozyme release of leukocytes in vitro and the blanching response of forearm skin to budesonide. A large number of secondary variables (urinary and plasma steroid measurements, blood pressure and indices of body fat metabolism, and routine biochemical and hematological measurements) were also considered. In vivo sensitivity to budesonide was greater in AA than aa individuals (mean +/- SE EC50 values: 13 +/- 5 and 42 +/- 10 ng; P < 0.01). In contrast, leukocytes of AA subjects tended to have lower affinity and reduced sensitivity for dexamethasone, although these effects were not statistically significant. Based on urinary steroid measurements, 11 beta-hydroxysteroid dehydrogenase activity [ratio of tetrahydrocortisol (THF) to tetrahydrocortisone (THE) metabolites] was not affected by genotype. The relative activities of 5 alpha- and 5 beta-reductase activity (allo-THF/THF + THE) appeared lower in AA than aa subjects (0.22 +/- 0.04 cf. 0.33 +/- 0.06; P < 0.005) but were not judged to be significantly different when corrected for multiple comparisons. Single and multivariate analyses were carried out to determine which variables influence GR binding characteristics and glucocorticoid responsiveness and to see whether cardiovascular risk factors (blood pressure and body fat) were influenced by glucocorticoid-dependent functions. Only 15-20% of the variations in the dissociation constant (Kd) and maximum binding capacity (Bmax) were influenced by other variables; plasma cholesterol was the most important for affinity and plasma sodium concentration for binding capacity. Multivariate analysis showed that several factors including GR genotype and urinary cortisol account for 10% of the variation of in vivo responses to glucocorticoid hormones; plasma calcium concentration was the only variable that contributed to in vitro sensitivity of leukocytes to dexamethasone. Glucocorticoid-dependent responses were of negligible importance in determining blood pressure or percentage body fat within the narrow physiological ranges of the present study. We conclude that GR genotype affects steroid sensitivity in a tissue-specific manner because of altered GR function or possibly because of linkage to a locus that controls hormone access to the receptor by influencing steroid metabolism.

Abstract —The association between hypertension and insulin resistance might be explained by increased activity of the principal glucocorticoid, cortisol. Recent data show that the intensity of dermal vasoconstriction after topical application of glucocorticoids is increased in patients with essential hypertension. In this report, we examine whether increased glucocorticoid sensitivity or secretion is associated with insulin resistance and is a cause or consequence of hypertension. We studied 32 men (aged 47 to 56 years) from a cross-sectional study and 105 men (aged 23 to 33 years) in whom predisposition to high blood pressure has been defined by their own blood pressure and the blood pressures of their parents. In both populations, increased dermal glucocorticoid sensitivity was associated with relative hypertension, insulin resistance, and hyperglycemia. In young men with higher blood pressure whose parents also had high blood pressure, enhanced glucocorticoid sensitivity was accompanied by enhanced secretion of cortisol, enhanced ligand-binding affinities for dexamethasone in leukocytes, and impaired conversion of cortisol to inactive metabolites (cortisone and 5β-dihydrocortisol). Increased tissue sensitivity to cortisol, amplified by enhanced secretion of cortisol, is a feature of the familial predisposition to high blood pressure rather than a secondary effect of high blood pressure. It may be mediated by an abnormal glucocorticoid receptor, and it may contribute to the association between hypertension and insulin resistance.

Abstract We compared glucocorticoid receptor binding characteristics and glucocorticoid responsiveness of human mononuclear leukocytes (HML) from hypertensive patients and matched normotensive volunteers. We also considered associations of these variables with plasma renin activity, aldosterone, cortisol, corticotropin, and electrolyte concentrations. We calculated binding affinity ( K d ; nmol/L) and capacity ( B max ; sites/cell) for dexamethasone and cortisol from homologous and heterologous competition curves for specific [ 3 H]dexamethasone binding sites on HML isolated from the blood of normotensive volunteers and subjects with essential hypertension. Glucocorticoid responsiveness of HML was evaluated as IC 50 values (nmol/L) for dexamethasone and cortisol for the inhibition of lysozyme release. We measured plasma hormones by radioimmunoassay. K d values (mean±SE) for cortisol in HML of hypertensive patients were higher than in control subjects (24.6±2.4 versus 17.5±1.7 nmol/L, P K d values for dexamethasone (6.7±0.5 versus 5.7±0.3 nmol/L), and IC 50 values for dexamethasone (3.4±0.3 versus 3.1±0.2 nmol/L) and cortisol (12.2±1.6 versus 9.5±0.3 nmol/L) were not significantly different. Patients with renin values less than 0.13 ng angiotensin I/L per second were markedly less sensitive to cortisol than those with higher values. Both K d (30.3±2.5 versus 19.2±2.4 nmol/L) and IC 50 values (15.5±1.8 versus 8.9±1.2 nmol/L) for cortisol were significantly higher in patients with lower renin values ( P

A 65-year-old woman presented to the endocrine clinic with increasing facial hirsutism over the past 6 months. She was noted to have excess hair on forearms, back and abdomen, along with some frontal balding. There were no abnormalities of the external genitalia, blood pressure was satisfactory and weight was stable. Biochemistry confirmed elevated testosterone (4.1 nmol/l). No abnormalities were seen on CT of abdomen and pelvis, nor by transvaginal ultrasound of the ovaries. Six months after her initial clinic visit, testosterone had increased to 6.0 nmol/l, rising to 7.3 nmol/l a few months later. Testosterone failed to suppress to low-dose dexamethasone suggesting excessive adrenal production was unlikely. Urine steroid profiling revealed no abnormality of adrenal steroid metabolites. Testosterone suppression was achieved with a rapidly-acting luteinizing-hormone-releasing hormone antagonist (cetrorelix), suggesting an ovarian source of excess production. Histology following bilateral salpingo-oophorectomy revealed a benign 6 mm diameter Leydig cell tumour in the right ovary.

A 16-year-old female with mild hirsutism was noted to have a small, smooth, non-tender goitre. A resting peripheral tremor, but no other symptoms or signs of thyroid dysfunction were present. Her only medication was the contraceptive pill. There was no family history of thyroid disease. Investigation showed elevated free thyroxine (28 pmol/l) and total triiodothyronine (3.4 nmol/l) with non-suppressed thyroid stimulating hormone (1.4 mU/l). Radioiodine uptake scan of the thyroid showed bilateral increased tracer uptake, suggestive of Graves’ disease, however thyroid peroxidase and antithyroid stimulating hormone (TSH) receptor antibody testing was negative and sex hormone binding globulin concentration was normal. Laboratory analyses excluded assay artefact or abnormal circulating thyroid hormone binding proteins. Genetic analysis identified a thyroid hormone receptor gene mutation (T277I), making a diagnosis of resistance to thyroid hormone (RTH). RTH is a disorder characterised by elevated thyroid hormones, failure to suppress pituitary TSH secretion and variable refractoriness to hormone action in peripheral tissues.

Nine hundred and ninety patients, ages 20 years or older, undergoing non-cardiac elective surgery were prospectively studied to identify high cardiac risk preoperative factors in a case-mix population and to assess cardiological risk. The prevalence of major cardiac complications was 2.3%, including 0.8% mortality. Univariate analysis showed that: age; history of chest pain; dyspnea; hypertension; presence of systolic murmur and third sound; diastolic pressure greater than 95 mmHg; electrocardiogram left ventricular hypertrophy; cardiothoracic ratio greater than 0.5 and valvular calcifications are associated with cardiac complications (p = 0.001-0.02), with low sensitivity (range: 14-38%) and high specificity (range: 85-98%). Cardiological referral was required for 169 patients (17%) that showed a higher prevalence of cardiovascular diseases (85%) and of cardiac complications (5.3%). Cardiologists required further tests for 13 patients (7.7%) and modified therapy for 93 (55%). High cardiac risk patients are identified preoperatively in current practice and cardiological referral is frequent; further studies are mandatory to evaluate the most effective and efficacious procedures.

Background The typical pattern of thyroid function tests (TFTs) associated with hypopituitarism consists of subnormal free T4 (fT4) or total T4 and normal or marginally elevated thyroid-stimulating hormone (TSH). A previous study calculated an incidence of hypopituitarism of 3.2 cases/100,000/year by following up abnormal TFTs. The aim of this study was to verify the incidence of unsuspected hypopituitarism diagnosed by reflective testing on such samples in a Scottish population. Methods Prospective audit of TFT results over 15 months. Individuals with suitable results (fT4 < 9 pmol/L, TSH < 10 mU/L) were identified by the laboratory information system at the Biochemistry Department, Glasgow Royal Infirmary, serving a population of 200,000. fT4 (repeat analysis following assay recalibration), total T3, testosterone (males), luteinizing hormone, follicle-stimulating hormone, prolactin and cortisol were analysed on appropriate samples. Results Three hundred and eleven suitable results from 266 adult individuals were identified from a total of 73,650 TFT results, leading to the diagnosis of 10 new cases (age range 28–90 years) of hypopituitarism (approximately 4 cases/100,000/year). Nine patients now attend endocrine clinics. Pituitary imaging was abnormal in five cases (2 large pituitary tumours, one macroadenoma, 2 empty sellae), normal in three cases and two patients were not scanned. Conclusions A significant number of cases of unsuspected hypopituitarism can be diagnosed by reflective testing on appropriate samples. fT4 should be an integral part of frontline TFTs as TSH alone cannot assist in the identification of possible hypopituitarism. Laboratories are in an excellent position to assist in early identification of hypopituitarism, which may lead to improved outcomes in such patients.

Glucocorticoid receptor binding was compared in liver cytosol preparations from spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats using homologous displacement of [3H]dexamethasone. At 5 degrees C, there was no difference in receptor binding affinity or concentration between strains for dexamethasone, corticosterone or aldosterone. At 37 degrees C, affinity for dexamethasone was lower than at 5 degrees C for both rat strains and decreased with time. However, at this higher temperature, binding affinity in the SHR preparation was consistently higher than in the WKY preparation. The WKY preparation had a higher receptor concentration. The rate of dissociation of the [3H]dexamethasone-receptor complex prepared at 5 degrees C and then incubated at 37 degrees C was rapid but not different between strains. A possible explanation of these results is that the relationship of the heat shock proteins to the receptor heterocomplex is different between strains. Evidence exists of a genetic difference in Hsp 70 between SHR and WKY rats, although its cosegregation with blood pressure has not been established.

HMG-CoA reductase inhibitors (statins) block the mevalonate pathway, preventing biosynthesis of cholesterol and isoprenoids. We investigated the effect of simvastatin on lymphocytes from normal human subjects and cardiovascular disease patients in order to provide a model for the in vivo actions of statins. Thirteen healthy volunteers were treated with 40 mg per day of simvastatin following which mean total cholesterol was reduced by 23% (S.D.+/- 11.7%) and mean LDL-cholesterol by 36% (S.D.+/- 16.3%). Lymphocyte lipid raft levels, represented by Lyn and Fyn, were also reduced by simvastatin. Treatment with simvastatin did not alter ex vivo T-lymphocyte proliferation. However, the in vitro addition of 1 microM simvastatin reduced T-lymphocyte proliferation by 39% (S.D.+/- 18.1%) and a combination of prenyl transferase inhibitors reduced proliferation by 19% (S.D.+/- 22.7%). We also assessed the cytotoxicity of natural killer (NK) cells-a T-lymphocyte subset. NK cell cytotoxicity ex vivo was reduced by 30% (S.D.+/- 33.6%) following oral simvastatin treatment and by 56% (S.D.+/- 24.68%) after the in vitro addition of 1 microM simvastatin. Significant ex vivo reductions in T-cell proliferation and NK cell cytotoxicity were observed in patients with cardiovascular disease on treatment with statins. NK cells have been implicated in the pathogenesis of atherosclerosis, so the effect of statin therapy on NK cell cytotoxicity may contribute to the benefits of statins in cardiovascular disease.

In 45 patients with essential hypertension and 15 age-matched normotensive control subjects, the renal resistive index, as an expression of arterial impedance, was determined using Doppler ultrasound. In both kidneys the resistive index was assessed at baseline and after captopril test (50 mg orally). In the moderate and severe hypertensives, compared to mild hypertensives and control subjects, the baseline resistive index was significantly higher (P less than .05). Following captopril, the resistive index increased only in normotensives (P less than .05) and in mild hypertensives (P less than .05). Univariate and multivariate analyses show that the duration and severity of hypertension correlated with an increase of the resistive index both in basal and in dynamic conditions. Thus, the use of the resistive index, as determined by echo-Doppler, could provide useful information for the assessment of renal vascular impedance in essential hypertensive patients. This would help us detect the evolution of hypertensive disease to the higher degrees of severity that are correlated to renal arteriolar damage.

Endothelin-1, a potent vasoconstrictor peptide with 21 amino acid residues, is released by the vascular endothelium. Plasma immunoreactive endothelin levels were measured in 23 patients with cirrhosis and in 20 healthy subjects. Concentrations were significantly lower in patients with non-uraemic cirrhosis than in normal subjects (19.4 +/- 8.9 pmol/l vs. 48.8 +/- 24.8 pmol/l, p less than 0.002). Plasma renin, aldosterone, atrial natriuretic peptide, arginine-vasopressin and catecholamines did not show significant correlations with plasma endothelin-1 levels. Furthermore, there were no significant differences in plasma endothelin levels for etiology of cirrhosis, presence of ascites or varices. These data suggest that low circulating endothelin may be involved in the development or maintenance of systemic vasodilatation in cirrhosis.