Parathyroidectomy for adults with primary hyperparathyroidism.

BACKGROUND: Primary hyperparathyroidism (PHPT), a disorder in which the parathyroid glands produce excessive amounts of parathyroid hormone, is most common in older adults and postmenopausal women. While most people with PHPT are asymptomatic at diagnosis, symptomatic disease can lead to hypercalcaemia, osteoporosis, renal stones, cardiovascular abnormalities and reduced quality of life. Surgical removal of abnormal parathyroid tissue (parathyroidectomy) is the only established treatment for adults with symptomatic PHPT to prevent exacerbation of symptoms and to be cured of PHPT. However, the benefits and risks of parathyroidectomy compared to simple observation or medical therapy for asymptomatic and mild PHPT are not well established. OBJECTIVES: To evaluate the benefits and harms of parathyroidectomy in adults with PHPT compared to simple observation or medical therapy. SEARCH METHODS: We searched CENTRAL, MEDLINE, LILACS, ClinicalTrials.gov and WHO ICTRP from their date of inception until 26 November 2021. We applied no language restrictions. SELECTION CRITERIA: We included randomised controlled trials (RCTs) comparing parathyroidectomy with simple observation or medical therapy for the treatment of adults with PHPT. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Our primary outcomes were 1. cure of PHPT, 2. morbidity related to PHPT and 3. serious adverse events. Our secondary outcomes were 1. all-cause mortality, 2. health-related quality of life and 3. hospitalisation for hypercalcaemia, acute renal impairment or pancreatitis. We used GRADE to assess the certainty of the evidence for each outcome. MAIN RESULTS: We identified eight eligible RCTs that included 447 adults with (mostly asymptomatic) PHPT; 223 participants were randomised to parathyroidectomy. Follow-up duration varied from six months to 24 months. Of the 223 participants (37 men) randomised to surgery, 164 were included in the analyses, of whom 163 were cured at six to 24 months (overall cure rate 99%). Parathyroidectomy compared to observation probably results in a large increase in cure rate at six to 24 months follow-up: 163/164 participants (99.4%) in the parathyroidectomy group and 0/169 participants in the observation or medical therapy group were cured of their PHPT (8 studies, 333 participants; moderate certainty).  No studies explicitly reported intervention effects on morbidities related to PHPT, such as osteoporosis, osteopenia, kidney dysfunction, urolithiasis, cognitive dysfunction or cardiovascular disease, although some studies reported surrogate outcomes for osteoporosis and cardiovascular disease. A post-hoc analysis revealed that parathyroidectomy, compared to observation or medical therapy, may have little or no effect after one to two years on bone mineral density (BMD) at the lumbar spine (mean difference (MD) 0.03 g/cm2,95% CI -0.05 to 0.12; 5 studies, 287 participants; very low certainty). Similarly, compared to observation, parathyroidectomy may have little or no effect on femoral neck BMD after one to two years (MD -0.01 g/cm2, 95% CI -0.13 to 0.11; 3 studies, 216 participants; very low certainty). However, the evidence is very uncertain for both BMD outcomes. Furthermore, the evidence is very uncertain about the effect of parathyroidectomy on improving left ventricular ejection fraction (MD -2.38%, 95% CI -4.77 to 0.01; 3 studies, 121 participants; very low certainty). Four studies reported serious adverse events. Three of these reported zero events in both the intervention and control groups; consequently, we were unable to include data from these three studies in the pooled analysis. The evidence suggests that parathyroidectomy compared to observation may have little or no effect on serious adverse events (RR 3.35, 95% CI 0.14 to 78.60; 4 studies, 168 participants; low certainty).  Only two studies reported all-cause mortality. One study could not be included in the pooled analysis as zero events were observed in both the intervention and control groups. Parathyroidectomy compared to observation may have little or no effect on all-cause mortality, but the evidence is very uncertain (RR 2.11, 95% CI 0.20 to 22.60; 2 studies, 133 participants; very low certainty). Three studies measured health-related quality of life using the 36-Item Short Form Health Survey (SF-36) and reported inconsistent differences in scores for different domains of the questionnaire between parathyroidectomy and observation. Six studies reported hospitalisations for the correction of hypercalcaemia. Two studies reported zero events in both the intervention and control groups and could not be included in the pooled analysis. Parathyroidectomy, compared to observation, may have little or no effect on hospitalisation for hypercalcaemia (RR 0.91, 95% CI 0.20 to 4.25; 6 studies, 287 participants; low certainty). There were no reported hospitalisations for renal impairment or pancreatitis. AUTHORS' CONCLUSIONS: In accordance with the literature, our review findings suggest that parathyroidectomy, compared to simple observation or medical (etidronate) therapy, probably results in a large increase in cure rates of PHPT (with normalisation of serum calcium and parathyroid hormone levels to laboratory reference values). Parathyroidectomy, compared with observation, may have little or no effect on serious adverse events or hospitalisation for hypercalcaemia, and the evidence is very uncertain about the effect of parathyroidectomy on other short-term outcomes, such as BMD, all-cause mortality and quality of life. The high uncertainty of evidence limits the applicability of our findings to clinical practice; indeed, this systematic review provides no new insights with regard to treatment decisions for people with (asymptomatic) PHPT. In addition, the methodological limitations of the included studies, and the characteristics of the study populations (mainly comprising white women with asymptomatic PHPT), warrant caution when extrapolating the results to other populations with PHPT. Large-scale multi-national, multi-ethnic and long-term RCTs are needed to explore the potential short- and long-term benefits of parathyroidectomy compared to non-surgical treatment options with regard to osteoporosis or osteopenia, urolithiasis, hospitalisation for acute kidney injury, cardiovascular disease and quality of life.

Artificial Intelligence-Assisted Loop Mediated Isothermal Amplification (AI-LAMP) for Rapid Detection of SARS-CoV-2.

Until vaccines and effective therapeutics become available, the practical solution to transit safely out of the current coronavirus disease 19 (CoVID-19) lockdown may include the implementation of an effective testing, tracing and tracking system. However, this requires a reliable and clinically validated diagnostic platform for the sensitive and specific identification of SARS-CoV-2. Here, we report on the development of a de novo, high-resolution and comparative genomics guided reverse-transcribed loop-mediated isothermal amplification (LAMP) assay. To further enhance the assay performance and to remove any subjectivity associated with operator interpretation of results, we engineered a novel hand-held smart diagnostic device. The robust diagnostic device was further furnished with automated image acquisition and processing algorithms and the collated data was processed through artificial intelligence (AI) pipelines to further reduce the assay run time and the subjectivity of the colorimetric LAMP detection. This advanced AI algorithm-implemented LAMP (ai-LAMP) assay, targeting the RNA-dependent RNA polymerase gene, showed high analytical sensitivity and specificity for SARS-CoV-2. A total of ~200 coronavirus disease (CoVID-19)-suspected NHS patient samples were tested using the platform and it was shown to be reliable, highly specific and significantly more sensitive than the current gold standard qRT-PCR. Therefore, this system could provide an efficient and cost-effective platform to detect SARS-CoV-2 in resource-limited laboratories.

Circulating microRNA in cardiovascular disease.

Acute myocardial infarction (AMI) and heart failure (HF) are two major causes of cardiovascular mortality and morbidity. Early diagnosis of these conditions is essential to instigate immediate treatment that may result in improved outcomes. Traditional biomarkers of AMI include cardiac troponins and other proteins released from the injured myocardium but there are a number of limitations with these biomarkers especially with regard to specificity. In the past few years circulating nucleic acids, notably microRNA that are small non-coding RNAs that regulate various cellular processes, have been investigated as biomarkers of disease offering improved sensitivity and specificity in the diagnosis and prognostication of various conditions. In this review, the role of microRNAs as biomarkers used in the diagnosis of AMI and HF is discussed, their advantage over traditional biomarkers is outlined and the potential for their implementation in clinical practice is critically assessed.

Primary hyperparathyroidism: findings from the retrospective evaluation of cases over a 6-year period from a regional UK centre.

BACKGROUND: Although there are international guidelines on diagnosis and management of primary hyperparathyroidism (PHPT), clinical practice varies in different centres. Periodic review of diagnostic work-up, surgical treatment by parathyroidectomy (PTX) and clinical surveillance in nonsurgical treatment group among patients with PHPT is expected to improve the quality of care. We report a retrospective study of cases with PHPT managed at a regional centre in the United Kingdom. METHODS: Clinical data of cases with calcium ≥2.6 mmol/L and parathyroid hormone (PTH) ≥9.0 pmol/L was procured from biochemistry database from January 2011 to December 2016. Laboratory parameters, imaging studies for renal stones, osteoporosis and localisation of parathyroid adenomas, type of treatment received (PTX or nonsurgical), complications of treatment, other medical co-morbidities and mortality during follow-up was recorded in each case to examine the outcomes of care of patients with PHPT. RESULTS: The study included 160 patients: 127 (79%) females and 33 (21%) males. Median age was 70 years in females and 74 in males. Thirty cases (19% of 159) had renal stones and 47 (37.3% of 126) had osteoporosis. Eighty-one cases (51%) received PTX. Logistic regression analysis showed that higher calcium levels (odds ratio (OR) = 73.991; p < 0.001), peak PTH (OR = 1.023; p = 0.025), peak alkaline phosphatase (OR = 0.985, p < 0.001), lower age (OR = 0.985, p < 0.001) and male gender (OR = 0.209, p < 0.002) as statistically significant predictors for patients receiving PTX. Higher age at diagnosis of PHPT was associated with increased risk of co-existent hypertension (OR = 10.904, p = 0.001) and fractures (OR = 1.067, p = 0.004). Higher peak calcium concentration was an independent predictor of acute kidney injury (OR = 9.631, p = 0.011). PTX cured 76 cases (94%) with only 7 (9%) postoperative complications. Twenty-four cases (15%) died from the entire cohort (only one from PTX group) during a median follow-up period of 3.6 years (interquartile range = 1.5). CONCLUSIONS: PTX treatment is associated with cure of disease in patients with PHPT with acceptable risk of complications. Improvements in diagnostic work-up and follow-up care should improve the morbidity from PHPT.

Pheochromocytomas and Hypertension.

PURPOSE OF REVIEW: Pheochromocytomas and paragangliomas (PPGLs) are uncommon catecholamine-producing neuroendocrine neoplasms that usually present with secondary hypertension. This review is to update the current knowledge about these neoplasms, the pathophysiology, genetic aspects and diagnostic and therapeutic algorithms based on scientific literature mostly within the past 3 years. RECENT FINDINGS: Eighty to eighty-five percent of PPGLs arise from the adrenal medulla (pheochromocytomas; PCCs) and the remainder from the autonomic neural ganglia (paragangliomas; PGLs). Catecholamine excess causes chronic or paroxysmal hypertension associated with sweating, headaches and palpitations, the presenting features of PPGLs, and increases the cardiovascular morbidity and mortality. Genetic testing should be considered in all cases as mutations are reported in 35-40% of cases; 10-15% of PCCs and 20-50% of PGLs can be malignant. Measurements of plasma-free metanephrines or 24-h urine-fractionated metanephrines help biochemical diagnosis with high sensitivity and specificity. Initial anatomical localization after biochemical confirmation is usually with computed tomography (CT) or magnetic resonance imaging (MRI). 123Iodine metaiodobenzylguanidine (123I-MIBG) scintigraphy, positron emission tomography (PET) or single-photon emission computed tomography (SPECT) is often performed for functional imaging and prognostication prior to curative or palliative surgery. Clinical and biochemical follow-up is recommended at least annually after complete tumour excision. Children, pregnant women and older people have higher morbidity and mortality risk. De-bulking surgery, chemotherapy, radiotherapy, radionuclide agents and ablation procedures are useful in the palliation of incurable disease. PPGLs are unique neuroendocrine tumours that form an important cause for endocrine hypertension. The diagnostic and therapeutic algorithms are updated in this comprehensive article.

Lean polycystic ovary syndrome (PCOS): an evidence-based practical approach.

BACKGROUND: Polycystic ovary syndrome (PCOS) is a common endocrinopathy affecting women of reproductive age. Common features include menstrual irregularities, hyperandrogenism and polycystic ovarian morphology although the presentation can be heterogeneous. Insulin resistance is thought to be responsible for the hormonal and metabolic derangements observed. PCOS has two phenotypes, overweight/obese and lean, the latter being a much less common presentation of the syndrome. AIMS: The aim of the present review is to summarise cardinal features, and to devise diagnostic and treatment algorithms for lean PCOS based on recent literature. METHODS: We searched PubMed, EBSCOhost and Google Scholar using search terms such as 'lean polycystic ovary syndrome' OR 'lean polycystic ovarian syndrome' OR 'lean PCOS' OR 'lean polycystic ovary disease' OR 'lean polycystic ovarian disease' OR 'lean PCOD' OR 'hyperandrogenism' AND 'low BMI OR 'low body mass index' to identify potential articles to be included in the review. Citation searches were subsequently performed in order to find relevant literature. RESULTS: Hormonal, metabolic and haematological profiles were altered in lean women with PCOS compared to healthy counterparts. However, the derangements were either comparable or less obvious compared to obese women with the syndrome. Insulin resistance seemed inherent in PCOS independent of obesity. Treatment options included weight maintenance, restoration of ovulation with insulin-sensitizers such as metformin, relief of symptoms such as hirsutism, acne and menstrual dysfunction, and assisted reproductive technologies in refractory cases, all of which showed promising results. The literature with evidence on lean PCOS is of low to moderate quality and there are still some uncertainties in the evidence base. CONCLUSION: Carefully designed randomised controlled trials are required to confirm findings of previous studies in lean PCOS and to consolidate diagnostic and management algorithms proposed in this review. This paper will aid health professionals to improve their clinical approach in managing lean women with PCOS.

Relationship between circulating microRNA-30c with total- and LDL-cholesterol, their circulatory transportation and effect of statins.

BACKGROUND: Small non-coding microRNAs (miR) have important regulatory roles and are used as biomarkers of disease. We investigated the relationship between lipoproteins and circulating miR-30c, evaluated how they are transported in circulation and determined whether statins altered the circulating concentration of miR-30c. METHODS: To determine the relationship between lipoproteins and circulating miR-30c, serum samples from 79 subjects recruited from a lipid clinic were evaluated. Ultracentrifugation and nanoparticle tracking analysis was used to evaluate the transportation of miR-30c in the circulation by lipoproteins and extracellular vesicles in three healthy volunteers. Using archived samples from previous studies, the effects of 40mg rosuvastatin (n=22) and 40mg pravastatin (n=24) on miR-30c expression was also examined. RNA extraction, reverse transcription-quantitative real-time polymerase chain reaction was carried out using standard procedures. RESULTS: When stratified according to total cholesterol concentration, there was increased miR-30c expression in the highest compared to the lowest tertile (p=0.035). There was significant positive correlation between miR-30c and total- (r=0.367; p=0.002) and LDL-cholesterol (r=0.391; p=0.001). We found that miR-30c was transported in both exosomes and on HDL3. There was a 3.8-fold increased expression of circulating miR-30c after pravastatin treatment for 1year (p=0.005) but no significant change with atorvastatin after 8weeks (p=0.145). CONCLUSIONS: This study shows for the first-time in humans that circulating miR-30c is significantly, positively correlated with total- and LDL-cholesterol implicating regulatory functions in lipid homeostasis. We show miR-30c is transported in both exosomes and on HDL3 and pravastatin therapy significantly increased circulating miR-30c expression adding to the pleiotropic dimensions of statins.

The association of circulating microRNA-30c with atherogenic lipoprotein subfractions and composition.

Circulating miR-30c has been linked to various aspects of cholesterol homeostasis. The aim of this study was to determine the association of circulating miR-30c with the atherogenic lipoprotein subfractions. Samples from subjects who were given placebo (n=22) in a randomised, double-blind crossover study were used. Subjects were divided into non-atherogenic lipoprotein phenotype (Non-ALP; n=12; triglycerides <2.0mmol/L) and atherogenic lipoprotein phenotype (ALP; n=10; triglycerides ≥2.0mmol/L) groups. All lipid and lipoprotein measurements, RNA extraction and reverse transcription-quantitative real-time polymerase chain reaction were undertaken using standard procedures. Subjects with ALP weighed significantly more than their non-ALP counterparts (p=0.023). In the non-ALP group there was significant correlation between miR-30c and components within VLDL1, namely triglyceride which showed a negative association (p=0.035) whereas phospholipids and cholesterol-ester were both positively correlated (p=0.025 and 0.014, respectively). In contrast, in the ALP group there was a significant correlation between the expression of miR-30c and components within VLDL2, namely triglyceride, which was positively associated (p=0.013). This study reveals specificity with regards to the effect of miR-30c on VLDL subfractions based on the individual's lipoprotein phenotype and implicates roles for microsomal-triglyceride transfer-protein and cholesteryl-ester-transfer-protein in LDL and VLDL metabolism, respectively.

The phenomenon of seasonal pseudohypokalemia: effects of ambient temperature, plasma glucose and role for sodium-potassium-exchanging-ATPase.

OBJECTIVES: There is limited data regarding the phenomenon of seasonal pseudohypokalemia. We aimed to demonstrate the incidence of spurious hypokalemia during the summer months and to investigate the mechanism of cause. DESIGN AND METHODS: Potassium and glucose results from primary care and hospital patients were collected retrospectively for a period of 1 year to assess the incidence of pseudohypokalemia. Experiments were undertaken to confirm that this was a reversible in vitro phenomenon due to increased temperature mediated by sodium-potassium-exchanging-ATPase. RESULTS: Our data show an increased incidence of hypokalemia associated with increasing ambient temperature during June-August in samples from primary care but not in hospital samples. In a subset of patients, we showed that the repeat results were within or at the lower limit of the reference range. Experiments showed that this phenomenon was mediated by the sodium-potassium-exchanging-ATPase. CONCLUSIONS: There is an increased incidence of pseudohypokalemia during the summer (seasonal pseudohypokalemia) in samples from primary care and this is an in vitro pseudo-phenomenon mediated by sodium-potassium-exchanging-ATPase.

General practitioner (GP) cardiac troponin test requesting: findings from a clinical laboratory audit.

BACKGROUND: There is limited data and literature on the issue of cardiac troponin test requesting by general practitioners (GPs). It was therefore our aim to audit the cardiac troponin test requests made by GPs in our community with a view to develop an informed strategy for assay provision and reporting of results. METHODS: A retrospective audit was undertaken of data in our laboratory database for all cardiac troponin T (cTnT) tests requested by GPs between January and June 2005. A prospective audit was then carried out between July and December 2005 using the telephone interview method. The number and distribution of tests, the reasons for the request and the intended action by the GPs were quantified. RESULTS: Forty-five of 46 of the results of both the retrospective and prospective audits were negative based on the 99th percentile level with less than 10% imprecision (cTnT <0.03 microg/L). During the one-year study period, we had requests from 24 general practices with a mean and mode of two and one requests per general practice respectively. The most common reason for the request was found to be chest pain that had occurred more than 24 h ago. CONCLUSION: Bearing in mind the limitations of an audit study, our findings obviate the use of cTnT in general practice. We suggest that the laboratory should liase with the GP and advise referral for specialist care if clinical suspicion of acute coronary syndrome is high.

Experimental and computer modelling speciation studies of the effect of pH and phosphate on the precipitation of calcium and magnesium salts in urine.

BACKGROUND: pH and phosphate concentration are the major determinants of precipitation in urine of the salts of calcium and magnesium. This study aims to model the process of salt precipitation and establish whether the acidification of urine samples is necessary for the accurate measurement of calcium and magnesium in a clinical laboratory setting. METHODS: Urine samples were collected from 21 patients, aliquots were taken from each patient sample and the pH was adjusted to cover the range 2.0-10.0. The analytical and biological variation for each analyte was established and used to calculate percentage changes and critical differences. The critical difference was used to assess whether there was a significant difference between acidified and un-acidified samples. The JESS (Joint Expert Speciation System) thermodynamic computer-modelling program was used to predict the distribution of salt species formed with varying pH values and phosphate levels in simulated urine. RESULTS: The results showed that at a pH greater than 6.5, measured calcium, magnesium and phosphate significantly decreased as a result of precipitation (p<0.0001), although the critical difference was generally not exceeded. Computer modelling showed that both pH and phosphate concentration affected the distribution of salt species formed, as well as the precipitation patterns of calcium and magnesium phosphates. Overall, calcium phosphate precipitation tends to predominate at lower phosphate concentrations and at pH values below about 6.5, while both calcium and magnesium phosphate precipitation occur at higher phosphate concentrations and pH values greater than 6.5. CONCLUSIONS: For accurate analysis of these analytes in urine, the pH should be routinely measured and acidification should be undertaken prior to analysis if the pH is greater than 6.5. Based on the findings of this study, acidification or the lack of it does not result in a clinically significant change in calcium, magnesium and phosphate measured in urine. This study also predicted the likely salt species formed at varying urinary pH values and phosphate concentrations.

Can lithium-heparin plasma be used for protein electrophoresis and paraprotein identification?

INTRODUCTION: Lithium-heparin plasma is the most commonly used sample type in many hospitals, but it has been suggested that it is not suitable for protein electrophoresis due to the presence of fibrinogen, which can potentially mask a paraprotein band or be misconstrued as one. Here we aimed to demonstrate that lithium-heparin plasma samples could be used for protein electrophoresis and paraprotein typing without or with ethanol treatment to remove the fibrinogen. METHOD: A lithium-heparin sample from a patient with IgGlambda, IgGkappa, IgAlambda and IgAkappa myeloma, a non-specific polyclonal increase and a serum control were treated with ethanol prior to protein electrophoresis. Immunofixation electrophoresis was undertaken to investigate the effect of ethanol treatment on immunoglobulin and light chains. Nephelometry was undertaken to investigate whether ethanol treatment affected the quantification of IgG levels. Densitometric evaluation of proteins after electrophoresis was used to study whether ethanol treatment affected other serum proteins. An audit was also undertaken to ascertain the magnitude of the potential interference from the fibrinogen band in heparinized samples. RESULTS AND CONCLUSIONS: Ethanol treatment significantly but incompletely removed the fibrinogen in lithium-heparin plasma samples and did not affect the integrity of any of the proteins investigated. Even without ethanol treatment, lithium-heparin plasma can be used for protein electrophoresis and paraprotein identification as the instances of interference between fibrinogen and paraproteins was low (2.3%). In rare cases where there is uncertainty or ambiguity, immuno-fixation electrophoresis is recommended. This report has implications in terms of reducing costs and turn-around time as it prevents the need for requesting another serum sample from patients. This may be one step towards a universal sample for all tests.

Mechanism of interference by haemolysis in the cardiac troponin T immunoassay.

BACKGROUND: The cardiac troponins have been shown to be sensitive and specific biochemical markers of myocardial infarction and highly prognostic for future adverse events in patients with acute coronary syndromes. There have been reports suggesting that haemolysis causes a negative interference in the cardiac troponin T (cTnT) assay but the mechanism(s) involved remain unknown. Here we show the effects of haemolysis and haemoglobin per se on the cTnT assay. METHODS: The effect of haemolysis was studied by the addition of prepared haemolysate to serum samples with known and clinically relevant cTnT levels. The effect of haemoglobin was studied by the addition of haemoglobin of increasing concentrations and noting its effect on the level of cTnT measured. The effect of putative proteases was determined indirectly by incubating samples with spiked cTnT with various protease inhibitors and observing the changes in the measured cTnT levels. RESULTS: The results show that both haemolysis, which is the release of haemoglobin and corpuscular contents, and haemoglobin itself negatively interfere in the cTnT assay in a concentration-dependent manner, although the former had a greater magnitude of effect. On haemolysis, indirect evidence suggests that proteases are released which degrade the cTnT in serum, thus causing the decreased levels detected. Pepstatin A, a reversible inhibitor of aspartic proteinases, effectively inhibited the loss of cTnT in serum at 37 degrees C and pH 7.4 over a 48-h period. We found that at a haemoglobin level of 0.75 g/L, cTnT declined by more than 10% of the initial concentration, suggesting that falsely decreased levels due to haemolysis may significantly affect the clinical utility of the assay. CONCLUSIONS: Haemolysis, haemoglobin per se and possibly proteolysis play a role in the negative interference in cTnT assays. Measures to reduce this interference must be implemented.