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April 2011

Editor:
Michael Bissell, MD, PhD, MPH

Aldosterone/renin ratio in a healthy pediatric population Aldosterone/renin ratio in a healthy pediatric population

It is important to be able to diagnose primary aldosteronism (PA) because of its ability to induce hyperten-sion and because of the deleterious effects of aldosterone on various organs, including its effects on the heart and blood vessels via nonepithelial receptors, independent of changes in blood pressure. Research reported in 1976 suggested that simultaneous measurements of serum aldosterone (SA) concentration and plasma renin activity (PRA), as well as the aldosterone/renin ratio (ARR), would be useful as a potential screening test for PA. The prevalence of PA increased from less than one percent when hypokalemia was used for screening to close to 10 percent when the ARR was used, and this value was even higher in patients with severe or resistant hypertension. The ARR by itself, however, does not result in a definitive diagnosis of PA. A confirmatory test is necessary, and 30 to 50 percent of patients with a positive ARR could display aldosterone levels that are normally suppressed after such testing. Different groups have established the ARR cutoff in adults to be between 20 to 40 when SA is measured in nanograms per deciliter and PRA is measured in nanograms per milliliter per hour. However, this value has not been validated in children and adolescents. Data regarding the prevalence of PA and the normal parameters of the renin angiotensin system, especially the ARR, are unknown for pediatric nonhypertensive individuals. The authors postulated that, because of the high prevalence of PA in the general hypertensive population, PA may begin in the pediatric population prior to those patients developing hypertensive and vascular damage. Furthermore, up to four percent of school-aged children are hypertensive, and the magnitude of the burden of hypertension requires increased awareness, treatment, and control. These considerations support the need for greater efforts to demonstrate an underlying cause of hypertension in order to facilitate early specific treatment that might decrease cardiovascular risk and, in cases confirmed as having a genetic basis, to enable genetic counseling. The authors sought to establish SA, PRA, and ARR levels in a pediatric normotensive healthy population. They performed a cross-sectional study on 211 healthy normotensive children who were four to 16 years old. The study children were divided into two subgroups: those with hypertensive parents (NH; n=113) and those with normotensive parents (n=98). The authors collected blood samples for measuring serum aldosterone, plasma renin activity, aldosterone/renin ratio, and DNA. They investigated the chimeric CYP11B1/CYP11B2 gene by long-extension PCR in subjects with an aldosterone/renin ratio of 25 or more. Results were expressed as median values (Q1–Q3). The authors found that NH and normotensive parent groups were similar with regard to serum aldosterone levels (6.5 [3.6 to 9.0] versus 6.5 [2.9 to 9.7] ng/dL; P=0.968) and plasma renin activity (2.3 [1.6 to 3.1] versus 2.4 [1.7 to 3.7] ng/mL per hour; P=0.129). The aldosterone/renin ratio was higher in the NH group, but this difference did not reach statistical significance (2.8 [1.9 to 4.1] versus 2.5 [1.4 to 4.0]; P=0.104). The chimeric CYP11B1/CYP11B2 gene was detected in one subject from the NH group. The authors demonstrated that normal aldosterone/renin ratio values in a healthy pediatric population without NH were lower than those reported for an adult normotensive population.

Martinez-Aguayo A, Aglony M, Campino C, et al. Aldosterone, plasma renin activity and aldosterone/renin ratio in a normotensive healthy pediatric population. Hypertension. 2010;56:391–396.

Correspondence: Carlos Fardella at cfardella@med.puc.cl

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A novel thyroid-stimulating immunoglobulin bioassay in Graves disease A novel thyroid-stimulating immunoglobulin bioassay in Graves disease

The autoantibodies of clinical relevance in Graves disease stimulate the thyroid-stimulating hormone receptor and directly influence the metabolic activity of the thyroid gland, leading to hyperthyroidism. The TSH-receptor (TSH-R) stimulating Igs (TSIs) with inflammatory cytokines mediate metabolic changes in TSH-R–positive fibroblasts, target cells of orbital tissues, and supposedly lead to Graves orbitopathy. Identi-fying TSIs and differentiating them from nonfunctional TSH-R remain important goals. Tests for detecting TSH-R autoantibodies in Graves disease patients do no necessarily identify the pathogenic TSH-R antibodies that determine the clinical outcome of thyroid autoimmunity. Methods that measure the binding of antibodies in patient sera to TSH-R immobilized on the surface of plastic-coated tubes, plates, or beads display high analytical sensitivity and specificity. Unfortunately, these methods do not measure the functional activity of Igs, nor do they discriminate between Igs with stimulating, blocking, or neutral activity. Over the past 30 years, biological assays to detect TSI in the sera of Graves disease patients have been developed. These experimental cell-based systems assess TSI activity on human thyroid cells, FRTL-5 primary rat thyrocytes, or Chinese hamster ovary cells transfected with recombinant human TSH-R. The protocols involve several days of cell culture with cell lines that are not quality controlled and require measuring radioactive cAMP released into the supernatant of cell lysates. Despite these limitations, the monitoring of TSI in Graves disease patients undergoing treatment with antithyroid medication and B-cell depletion indicates a promising role for TSI bioassays in evaluating response to therapy. To assess the relevance of TSI in the pathogenesis of Graves disease and its extrathyroid manifestations, the authors performed a controlled cross-sectional trial in a large cohort of Graves disease subjects. They tested TSI in two reporter cell lines designed to measure Igs binding the TSH-R and transmitting signals for cAMP/CREB/cAMP regulatory element complex-dependent activation of luciferase gene expression. Responsiveness of the novel chimeric (Mc4) TSH-R (amino acid residues 262–335 of human TSH-R replaced by rat LH-R) to TSI was compared with the wild-type TSH-R. The authors found that all hyperthyroid Graves disease/Graves orbitopathy patients were TSI positive. TSIs were detected in 150 of 155 (97 percent, Mc4) and 148 of 155 (95 percent, wild type) Graves orbitopathy patients, six of 45 (13 percent, Mc4) and 20 of 45 (44 percent, wild type) mostly treated Graves disease subjects, and zero of 40 (Mc4) and one of 40 (wild type) controls. Serum TSI titers were three- and eight-fold higher in Graves orbitopathy than in Graves disease and control subjects, respectively. All patients with diplopia and optic neuropathy and smokers were TSI positive. TSI strongly correlated with Graves orbitopathy activity (r=0.87 and r=0.7; both, P<0.001) and severity (r=0.87 and r=0.72; both, P<0.001) in the Mc4 and wild-type bioassays, respectively. Clinical sensitivity (97 versus 77 percent; P<0.001) and specificity (89 versus 43 percent; P<0.001) of the Mc4/TSI were greater than TRAb in Graves orbitopathy. All 11 of 200 (5.5 percent) TSI-positive/TRAb-negative patients had Graves orbitopathy, whereas all seven of 200 (3.5 percent) TSI-negative/TRAb-positive subjects had Graves disease only. The authors concluded that the novel Mc4/TSI is a functional indicator of Graves orbitopathy activity and severity.

Lytton SD, Ponto KA, Kanitz M, et al. A novel thyroid stimulating immunoglobulin bioassay is a functional indicator of activity and severity of Graves’ orbitopathy. J Clin Endocrinol Metab. 2010;95:2123–2131.

Correspondence: George J. Kahaly at Kahaly@ukmainz.de

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Prevalence of cystic fibrosis after the introduction of newborn screening Prevalence of cystic fibrosis after the introduction of newborn screening

Newborn screening for cystic fibrosis was introduced in Victoria, Australia, in 1989 to facilitate early diagnosis and genetic counseling for parents of affected infants. All infants have a heel prick test on day two to four of life. They are initially screened for elevated serum levels of trypsinogen by immunoreactive assay (IRT). In the first two years of the screening program (1989–1990), a second IRT was requested at four to six weeks if the initial value was elevated (above the 99th centile of values), and the diagnosis was confirmed by a sweat test. Since 1991, gene-mutation analysis was incorporated into the screening program, testing for the common cystic fibrosis (CF) transmembrane conductance regulator (CFTR) gene mutation p.508del (1991–2006). In addition to detecting infants with CF, newborn screening also detects a number of healthy carriers. These infants have an elevated IRT, one CFTR gene mutation, and a normal sweat chloride value. The families of these infants are also offered genetic counseling and cascade family testing. Although the inherited nature of CF had been recognized for a long time, prior to 1989 there were limited options with regard to testing carrier parents and virtually no ability to offer prenatal testing to detect affected pregnancies. Identification of the CFTR gene and the mutations responsible for CF led to inclusion of gene mutation testing as part of the newborn screening paradigm and created a clear understanding among parents at the time of diagnosis that CF is a genetic condition and that testing of subsequent pregnancies was possible. The authors hypothesized that the live-birth prevalence of CF would decrease after the introduction of newborn screening as a result of carrier parents utilizing prenatal testing on subsequent pregnancies. They conducted a study to determine the live-birth prevalence of CF in the years before and after the introduction of newborn screening for CF. The authors reviewed the records of the Victoria, Australia, newborn screening program and the clinical records of the three centers caring for patients with CF in Victoria to determine the live-birth prevalence of patients with CF before (1979–1988) and after (1989–2006) the introduction of newborn screening. They also reviewed the records of the Victorian Clinical Genetics Service to ascertain the number and outcome of prenatal tests for CF between 1979 and 2006. They obtained records of live births in Victoria from the state birth register. Between 1979 and 1988, the live-birth prevalence of CF was 3.96 (95 percent confidence interval [CI], 3.48–4.49) per 10,000 live births. Following the introduction of newborn screening, the live-birth prevalence of CF was 3.28 (95 percent CI, 2.97–3.63) per 10,000 live births, representing a reduction of 17 percent (95 percent CI, 2–29 percent; P=0.025). In the prescreening period, there were 10 prenatal tests, which identified three affected pregnancies, all of which were terminated. In the later period, there were 304 prenatal tests (mean, 17 per year), of which 76 were affected, and 70 of these pregnancies were terminated. The authors concluded that there was a modest reduction in the live-birth prevalence of CF since the introduction of newborn screening. This is principally due to at-risk couples who were identified through newborn screening programs electing to use prenatal testing on subsequent pregnancies.

Massie J, Curnow L, Gaffney L, et al. Declining prevalence of cystic fibrosis since the introduction of newborn screening. Arch Dis Child. 2010;95:531–533.

Correspondence: Dr. John Massie at john.massie@rch.org.au

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Pro-adrenomedullin in acute myocardial infarction Pro-adrenomedullin in acute myocardial infarction

Identifying patients at high risk for adverse outcome after acute myocardial infarction remains a challenge. Circulating natriuretic peptide levels, such as N-terminal pro-B-type natriuretic peptide (NTproBNP), provide prognostic information regarding the risk of death and heart failure after acute myocardial infarction (AMI). The prognostic superiority of these biomarkers has been borne out in a range of acute coronary syndromes. Newer peptides are emerging that may give complementary and additional information, particularly in a multimarker strategy with NTproBNP. Adreno-medullin (ADM) is a 52-amino-acid peptide that has homology with calcitonin gene-related peptide. This peptide was originally isolated from human pheochromocytoma cells but subsequently has been detected in other tissues, including the adrenal medulla, heart, brain, lung, kidney, and gastrointestinal organs, and its mRNA is highly expressed in endo-thelial cells. The downstream actions of ADM are mediated by an increase in cyclic adenosine monophosphate (cAMP) levels, causing potent vasodilation and hypotension. ADM may also have autocrine or paracrine actions. Adrenomedullin is synthesized as part of the larger precursor molecule preproadreno-medullin. In humans, this precursor consists of 185 amino acids. The gene encoding preproadrenomedullin is termed the ADM gene and has been mapped and localized to chromosome 11. Adrenomedullin is difficult to measure in plasma because it is partially complexed with complement factor H and is rapidly cleared from the circulation. The more stable midregional fragment of proADM (MR-proADM), comprising amino acids 45 to 92 of preproADM, recently has been identified and is more stable than the active molecule being secreted in equimolar amounts to ADM. The biological activity of ADM in the cardiovascular system is similar to that of B-type natriuretic peptide (BNP), causing vasodilation via production of nitric oxide and increasing cardiac output, as well as inducing diuresis and natriuresis. Plasma ADM is increased in heart failure in proportion to the severity of disease and is inversely related to left ventricular ejection fraction. The potential role of the more stable prohormone MR-proADM in prognostication after AMI is unknown. The authors conducted a study to determine whether MR-proADM would be of benefit in determining prognosis after AMI, particularly for predicting death and heart failure. They compared it with NTproBNP, a peptide of established prognostic value in this group of patients. They measured plasma MR-proADM and NTproBNP in 983 consecutive post-AMI patients (721 men; mean age, 65.0 ± 12.2 years) three to five days after the onset of chest pain. The authors reported 101 deaths and 49 readmissions with heart failure during followup (median, 342; range, 0–764 days). The MR-proADM was increased in patients with death or heart failure compared with survivors (median, 1.19 nmol/L; range, 0.09–5.39 nmol/L versus 0.71 nmol/L; range, 0.25–6.66 nmol/L; P<0.0001). Using a multivariate binary logistic model, log MR-proADM (odds ratio, 4.22) and log NTproBNP (odds ratio, 3.20) were significant independent predictors of death or heart failure, along with creatinine, age, gender, and history of AMI. The areas under the receiver-operating characteristic curve for MR-proADM, NTproBNP, and the logistic model with both markers were 0.77, 0.79, and 0.84 respectively. Cox models for the predictors of death or heart failure showed the same variables (including log MR-proADM: hazard ratio, 3.63; log NTproBNP: hazard ratio, 2.67). The MR-proADM provided further risk stratification in those patients who had NTproBNP levels above the median (P<0.0001). Findings were similar for death and heart failure as individual end points. The authors concluded that the ADM system is activated after AMI. The MR-proADM is a powerful predictor of adverse outcome, especially in those with an elevated NTproBNP. The MR-proADM may represent a clinically useful marker of prognosis after AMI.

Khan SQ, O’Brien RJ, Struck J, et al. Prognostic value of midregional pro-adrenomedullin in patients with acute myocardial infarction. J Am Coll Cardiol. 2007;49:1525–1532.

Correspondence: Dr. Sohail Q. Khan at sqk1@le.ac.uk

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Clinical pathology abstracts editor: Michael Bissell, MD, PhD, MPH, professor, Department of Pathology, Ohio State University, Columbus.