Detecting patients with Cushing's syndrome: The importance of initial test selection.

BACKGROUND AND OBJECTIVES: The recommended initial tests for suspected Cushing's syndrome are late-night salivary cortisol (LNSC), 24-hour urinary free cortisol (UFC) and the 1 mg overnight dexamethasone suppression test (ONDST). These tests have higher sensitivity and specificity than serum cortisol. The aim of this study was to determine the relative frequency of these requested tests in primary care. METHOD: Initial test selection for investigation of Cushing's syndrome was audited by reviewing pathology request forms for cortisol tests made to a major community-based laboratory in 2019. Those with hypertension or adrenal incidentaloma as the documented indication for testing were included. RESULTS: In 214 of 272 cases (78.7%; 95% confidence interval: 73.2%, 83.3%) initial testing was by measurement of serum cortisol alone. DISCUSSION: The relatively infrequent selection of the higher sensitivity tests (ONDST, UFC and LNSC) for investigation of suspected Cushing's syndrome signifies a risk of delayed or missed diagnosis, with important implications for morbidity and mortality.

A case of pseudohyperchloraemia caused by sodium nitrate ingestion.

Emergency department presentations of sodium nitrate poisoning are increasing in frequency. Point-of-care blood gas analysis is useful for identifying methaemoglobinaemia and other abnormalities in such patients. Topically applied nitrate is known to positively interfere with chloride measurement in both point-of-care instruments and automated analysers of the clinical chemistry laboratory. In this article, the authors describe a case of pseudohyperchloraemia caused by sodium nitrate, which was consumed orally for the purpose of suicide. Consistent with the established pattern of interference, the ABL800 (Radiometer Medical, Brønshøj Copenhagen) blood gas analyser produced spuriously high chloride results, whilst the Alinity (Abbott Diagnostics, Abbot Park, Illinois) automated analyser resulted in chloride measurements comparable to those of inductively coupled mass spectrometry (ICP-MS). Both instruments, measure chloride with ion-selective electrodes (ISEs). The ABL800 (Radiometer) uses a membrane electrode, which is vulnerable to permeation by lipophilic nitrate ions, whereas the Alinity (Abbott) employs a silver chloride redox electrode system that is resistant to precipitation of silver nitrate due to its relatively high solubility. These mechanistic differences likely explain why nitrate interferes with some point-of-care devices but does not appear to affect the results of automated analysers.

Approach to the diagnosis of secondary hypertension in adults.

Presentations that should raise suspicion of secondary hypertension include early-onset, severe or resistant hypertension. A suggestive family history or clinical clues can point to a specific secondary cause. The most common causes and associations are renal disease, primary aldosteronism and obstructive sleep apnoea. Medicines, illicit substances and alcohol may also be responsible. The assessment of patients begins with history taking and examination, to look for clinical clues. Laboratory tests include electrolytes, urea, creatinine and the aldosterone:renin ratio, urinalysis and the urine albumin:creatinine ratio. Abnormal results should prompt further investigation. Initial testing for primary aldosteronism is best done before starting potentially interfering antihypertensive drugs. If the patient is already taking interfering antihypertensive drugs that cannot be stopped, the interpretation of the aldosterone:renin ratio must consider the presence of those drugs. Specialist advice can be sought if needed.

The Role of PINP in Diagnosis and Management of Metabolic Bone Disease.

Serum procollagen type I N-propeptide (PINP) is designated the reference marker of bone formation in osteoporosis; the reference marker for resorption is C-terminal telopeptide of type I collagen (CTX). PINP has very low circadian and biological variation, is not affected by food intake, and is very stable in serum after venepuncture. The two automated commercial assays for PINP provide similar results in subjects with normal renal function, allowing reference intervals to be used interchangeably. Bone turnover markers (BTM) are currently not recommended for fracture risk assessment and therefore not included in fracture risk calculators. In the management of osteoporosis, the main utility of BTM including PINP is for monitoring therapy, both antiresorptive as well as anabolic agents; monitoring is thought to help improve adherence. PINP as well as CTX may also be used in assessing offset of drug action following a pause in bisphosphonate therapy, to help decide when to re-instate therapy, or following cessation of denosumab therapy to assess efficacy of follow-on bisphosphonate therapy. PINP may also be used in the diagnosis of Paget's disease of bone as well as in monitoring response to therapy and for recurrence. Although BTM other than bone alkaline phosphatase are currently not recommended for use in metabolic bone disease of chronic kidney disease, PINP measured by assays specific to the intact molecule has potential in this condition. Further studies are needed to examine this area, as well as in malignant bone disease.

The challenge of improving the diagnostic yield from metanephrine testing in suspected phaeochromocytoma and paraganglioma.

Background Plasma-free metanephrines (PFM) or urinary fractionated metanephrines (UFM) are the preferred biochemical tests for the diagnosis of phaeochromocytoma and paraganglioma (PPGL). Borderline increased results should be followed up to either exclude or confirm diagnosis. Methods We extracted all PFM and UFM results reported by our laboratory over a six-month period from the laboratory information system. We categorized patients with borderline increased results according to whether follow-up testing had been performed as suggested in the initial laboratory report. Questionnaires were then sent to all requesting doctors and medical notes reviewed where available. Results Two hundred and four patients with borderline increased PFM or UFM were identified. Sixty-five (38.5%) of 169 patients with borderline increased PFM had a repeat test out of which 36 were normal and 29 did not normalize. Of 35 patients with borderline increased UFM, 17 (48.6%) had subsequent PFM measurement, out of which 15 were normal. Questionnaires were returned to 106 (52%) patients. Of these, the most frequent indication for testing was hypertension ( n = 50); 15 patients had an incidental adrenal mass and two of these patients were diagnosed with a phaeochromocytoma. Conclusion Only 38% of patients with borderline increased PFM had a repeat PFM measurement. This was not significantly higher when compared with the 28% in a previous audit that we reported in 2010 ( P = 0.10). Forty-nine per cent of patients with a borderline increased UFM had a repeat UFM or PFM measurement. There remains a substantial possibility of missed detection of PPGL.

Improved technical success and radiation safety of adrenal vein sampling using rapid, semi-quantitative point-of-care cortisol measurement.

Objective Primary aldosteronism is a curable cause of hypertension which can be treated surgically or medically depending on the findings of adrenal vein sampling studies. Adrenal vein sampling studies are technically demanding with a high failure rate in many centres. The use of intraprocedural cortisol measurement could improve the success rates of adrenal vein sampling but may be impracticable due to cost and effects on procedural duration. Design Retrospective review of the results of adrenal vein sampling procedures since commencement of point-of-care cortisol measurement using a novel single-use semi-quantitative measuring device for cortisol, the adrenal vein sampling Accuracy Kit. MEASUREMENTS: Success rate and complications of adrenal vein sampling procedures before and after use of the adrenal vein sampling Accuracy Kit. Routine use of the adrenal vein sampling Accuracy Kit device for intraprocedural measurement of cortisol commenced in 2016. Results Technical success rate of adrenal vein sampling increased from 63% of 99 procedures to 90% of 48 procedures ( P = 0.0007) after implementation of the adrenal vein sampling Accuracy Kit. Failure of right adrenal vein cannulation was the main reason for an unsuccessful study. Radiation dose decreased from 34.2 Gy.cm2 (interquartile range, 15.8-85.9) to 15.7 Gy.cm2 (6.9-47.3) ( P = 0.009). No complications were noted, and implementation costs were minimal. Conclusions Point-of-care cortisol measurement during adrenal vein sampling improved cannulation success rates and reduced radiation exposure. The use of the adrenal vein sampling Accuracy Kit is now standard practice at our centre.

Faecal Calprotectin.

Calprotectin is a calcium- and zinc-binding protein of the S-100 protein family which is mainly found within neutrophils and throughout the human body. The presence of calprotectin in faeces is a consequence of neutrophil migration into the gastrointestinal tissue due to an inflammatory process. Faecal calprotectin concentrations demonstrate good correlation with intestinal inflammation and faecal calprotectin is used as a biomarker in gastrointestinal disorders. Faecal calprotectin is a very sensitive marker for inflammation in the gastrointestinal tract, and useful for the differentiation of inflammatory bowel disease (IBD) from irritable bowel syndrome (IBS). Faecal calprotectin is used for the diagnosis, monitoring disease activity, treatment guidance and prediction of disease relapse and post-operative recurrence in IBD. There may also potentially be a role for faecal calprotectin in the management of infectious gastroenteritis, acute appendicitis, peptic ulcer disease, cystic fibrosis, coeliac disease, transplant rejection and graft versus host disease. Further studies are needed to confirm its utility in these conditions. Analysis of faecal calprotectin consists of an extraction step followed by quantification by immunoassay. Over the past few decades, several assays and extraction devices including point-of-care methods have been introduced by manufacturers. The manufacturer-quoted cut-off values for different faecal calprotectin assays are generally similar. However, the sensitivities and specificities at a given cut-off, and therefore the optimum cut-off values, are different between assays. A reference standard for calprotectin is lacking. Therefore, assay standardisation is required for more accurate and traceable test results for faecal calprotectin.

Quantifying the intraindividual variation of antimüllerian hormone in the ovarian cycle.

OBJECTIVE: To quantify intraindividual variability of antimüllerian hormone (AMH) as analytical and biological coefficients of variation and assess the effects of variation on clinical classification. DESIGN: Retrospective cohort study. SETTING: Not applicable. PATIENT(S): Thirty-eight women referred by general practitioners. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Total intraindividual variability (CVW), analytical (CVA) and biological variability (CVI) for each woman and for AMH ranges: low (<5 pmol/L), reduced (5-10), moderate (>10-30) and high (>30 pmol/L), with calculation of proportion of women crossing clinical cutoffs and expected variability around each cutoff. RESULT(S): Cycling women (n = 38) contributed 238 blood samples (average 6 samples each). The average total intraindividual AMH variability was 20% (range: 2.1% to 73%). Biological variation was 19% (range: 0 to 71%) and at least twice the analytical variation of 6.9% (range: 4.5% to 16%). Reclassification rates were highest in women with low (33%) or reduced AMH (67%) levels. Expected variations around the 5, 10, and 30 pmol/L cutoffs were 3-7, 7-13, and 20-40 pmol/L, respectively. In a woman with mean AMH in the 10-30 pmol/L range, the span of results that could occur was 7-40 pmol/L. CONCLUSION(S): Total variation in AMH was 20%, and the majority of this was biological. Changes in AMH resulted in reclassification in 29% of women and occurred most frequently in those with low and reduced AMH. In cycling women, the variability in AMH should be considered by clinicians, especially if a result is close to a clinical cutoff.

Serum 25-hydroxyvitamin D levels in vitamin D-insufficient hip fracture patients after supplementation with ergocalciferol and cholecalciferol.

Vitamin D insufficiency is commonly associated with hip fracture. However, the equipotency of ergocalciferol and cholecalciferol supplementation in this patient group has not been studied in a randomized trial using high-performance liquid chromatography (HPLC) measurement of serum 25-hydroxyvitamin D (25OHD). The objective of this study was to determine if ergocalciferol and cholecalciferol are equipotent therapies in vitamin D-insufficient hip fracture patients. Ninety five hip fracture inpatients with vitamin D insufficiency (25OHD<50 nmol/L) were randomized, double-blind, to treatment with ergocalciferol 1000 IU/day (n=48) or cholecalciferol 1000 IU/day (n=47) for three months. All participants were also given a placebo matching the alternative treatment to maintain blinding of treatment allocation. The primary endpoint was total serum 25OHD measured by HPLC. Secondary endpoints included 25OHD measured by radioimmunoassay (RIA), intact parathyroid hormone (iPTH), and bioactive (1-84) whole PTH (wPTH). Seventy patients (74%) completed the study with paired samples for analysis. Cholecalciferol supplementation resulted in a 31% greater increase in total HPLC-measured 25OHD (p=0.010) and 52% greater rise in RIA-measured 25OHD (p<0.001) than supplementation with an equivalent dose of ergocalciferol. Changes in iPTH and wPTH were not significantly different between calciferol treatments (p>0.05). In vitamin D-insufficient hip fracture patients, supplementation with cholecalciferol 1000 IU/day for three months was more effective in increasing serum 25OHD than an equivalent dose of ergocalciferol. However, the lack of difference in PTH lowering between calciferol treatments raises questions about the biological importance of this observation.

Directions for clinical practice improvement in HFE gene mutation testing.

OBJECTIVE: To audit the clinical indications for HFE gene mutation testing in a consecutive series of requests. DESIGN: Retrospective audit of reasons prompting 187 HFE test requests received between June 2003 and June 2005, by examination of the request form, hospital notes (when available) and, when required, information from the referring doctor. SETTING: A tertiary care public teaching hospital laboratory, Perth, Western Australia. MAIN OUTCOME MEASURES: Reasons prompting requests for HFE genotype testing and compliance with accepted clinical indications (biochemical evidence of iron overload on repeated samples, or a first-degree relative with either haemochromatosis or a C282Y mutation). RESULTS: Insufficient clinical details in requests prevented the inclusion of interpretive comments in HFE genotype reports in 70 of 187 cases (37%). Re-evaluation after collation of the missing details for all but seven requests revealed that 103 of the 180 auditable requests (57%) had been prompted for reasons other than biochemical evidence of iron accumulation or family history. CONCLUSIONS: A substantial proportion of HFE genotype test requests are made for inappropriate reasons. Clinical practice could be improved by educating doctors on the practical utility of this genetic test and by laboratories taking steps to secure the clinical information needed to include appropriate interpretive comments in their reports.

Clomiphene-associated combined hyperlipidemia: a case report.

BACKGROUND: Hyperlipidemia associated with clomiphene use is an uncommon but potentiallly serious complication of this therapy. Clomiphene is structurally similar to other synthetic estrogen analogs, which are known to induce marked hypertriglyceridemia. There is a paucity of data regarding the effects of clomiphene on lipid metabolism in humans. CASE: A 33-year-old woman with obesity, polycystic ovary syndrome and a long history of amenorrhea was treated with clomiphene therapy to induce ovulation. Baseline lipids were suggestive of an underlying lipid disorder, but there was a marked deterioration in her lipid profile in association with the use of clomiphene. On cessation of the clomiphene therapy her lipid profile slowly improved, and specific lipid-lowering therapy was not used. Further investigation for the possibility of an underlying lipid disorder confirmed the diagnosis of familial dysbetalipoproteinemia. CONCLUSION: Clomiphene should be used cautiously in women known to have dyslipidemia. We recommend that patients with predisposing risk factors have their lipids measured prior to ovulation induction with clomiphene.

Small changes in thyroxine dosage do not produce measurable changes in hypothyroid symptoms, well-being, or quality of life: results of a double-blind, randomized clinical trial.

CONTEXT: In patients with primary hypothyroidism, anecdotal evidence suggests that well-being is optimized by fine adjustment of T(4) dosage, aiming for a serum TSH concentration in the lower reference range. This has not been tested in a clinical trial. OBJECTIVE: Our objective was to test whether adjustment of T(4) dosage aiming for a serum TSH concentration less than 2 mU/liter improves well-being compared with a serum TSH concentration in the upper reference range. DESIGN: We conducted a double-blind, randomized clinical trial with a crossover design. PARTICIPANTS: Fifty-six subjects (52 females) with primary hypothyroidism taking T(4) (>/=100 microg/d) with baseline serum TSH 0.1-4.8 mU/liter participated. INTERVENTIONS: Each subject received three T(4) doses (low, middle, and high in 25-microg increments) in random order. OUTCOME MEASURES: Outcome measures included visual analog scales assessing well-being (the primary endpoint) and hypothyroid symptoms, quality of life instruments (General Health Questionnaire 28, Short Form 36, and Thyroid Symptom Questionnaire), cognitive function tests, and treatment preference. RESULTS: Mean (+/- sem) serum TSH concentrations were 2.8 +/- 0.4, 1.0 +/- 0.2, and 0.3 +/- 0.1 mU/liter for the three treatments. There were no significant treatment effects on any of the instruments assessing well-being, symptoms, quality of life, or cognitive function and no significant treatment preference. CONCLUSIONS: Small changes in T(4) dosage do not produce measurable changes in hypothyroid symptoms, well-being, or quality of life, despite the expected changes in serum TSH and markers of thyroid hormone action. These data do not support the suggestion that the target TSH range for the treatment of primary hypothyroidism should differ from the general laboratory range.

Urinary NTX results rarely alter the clinical management of patients with osteoporosis in the tertiary hospital.

AIM: Urinary levels of cross-linked N-terminal telopeptide of type I collagen (NTX) are used as a marker of bone resorption and are useful for monitoring response of patients treated with anti-resorptive agents. We aimed to determine how urinary NTX results alter clinical decision making by physicians treating patients with osteoporosis in a tertiary hospital setting. METHODS: We reviewed patient notes of all new NTX requests in 2002 and 2003 with at least one subsequent repeat measurement. Patients with a diagnosis of osteoporosis and both pre- and post-treatment measurements of bone mineral density (BMD) and NTX were included. Urinary NTX was measured with the Osteomark enzyme-linked immunosorbent assay. BMD of the hip and lumbar spine was measured using dual energy X-ray absorptiometry (DEXA). RESULTS: A total of 357 patients had serial NTX requests during the time period. Sixty-five of these patients had a diagnosis of osteoporosis. Out of 37 patients treated for osteoporosis who had complete data available, 29 patients had concordant results between BMD and NTX and eight patients had discordant results. Only one patient had treatment changed as a result of a lack of reduction in NTX following treatment. Thirteen patients had therapy altered. Common reasons for altering therapy were patient non-compliance, side effects and failure of BMD to increase. CONCLUSIONS: Alteration to therapy in this patient population is mainly dictated by issues such as patient compliance, medication side effects and bone mineral density results rather than urinary NTX values.

Thyrotoxic, hypokalaemic periodic paralysis.

Thyrotoxic, hypokalaemic periodic paralysis is an uncommon, potentially life-threatening endocrine emergency. Because of the acute onset of neurological symptoms patients often initially present to hospital ED. To reduce patient morbidity and costs of unnecessary investigations, early recognition and appropriate treatment is required. The case of a young man of Singaporean origin is presented to highlight current treatment, management and pathophysiology of this condition.

Alcohol-associated severe hyperhomocysteinaemia.

We report the cases of three men with severe hyperhomocysteinaemia that was associated with high alcohol intake and which resolved on reduction of alcohol intake. Investigation to identify other obvious causes of the hyperhomocysteinaemia excluded renal failure and vitamin deficiencies. Alcohol as a possible cause of significantly increased plasma homocysteine may be under-recognized by clinicians.