Andre Mattman

The 24-hour urine collection: gold standard or historical practice?

OBJECTIVE The objective of the study was to determine completeness of 24-hour urine collection in pregnancy. STUDY DESIGN This was a retrospective laboratory/chart review of 24-hour urine collections at British Columbia Womens Hospital. Completeness was assessed by 24-hour urinary creatinine excretion (UcreatV): expected according to maternal weight for single collections and between-measurement difference for serial collections. RESULTS For 198 randomly selected pregnant women with a hypertensive disorder (63% preeclampsia), 24-hour urine collections were frequently inaccurate (13-54%) on the basis of UcreatV of 97-220 micromol/kg per day (11.0-25.0 mg/kg per day) or 133-177 micromol/kg per day (15.1-20.1 mg/kg per day) of prepregnancy weight (respectively). Lean body weight resulted in more inaccurate collections (24-68%). The current weight was frequently unavailable (28%) and thus not used. For 161 women (81% proteinuric) with serial 24-hour urine levels, a median [interquartile range] of 11 [5-31] days apart, between-measurement difference in UcreatV was 14.4% [6.0-24.9]; 40 women (24.8%) had values 25% or greater, exceeding analytic and biologic variation. CONCLUSION Twenty-four hour urine collection is frequently inaccurate and not a precise measure of proteinuria or creatinine clearance.

Estimating Pediatric Glomerular Filtration Rates in the Era of Chronic Kidney Disease Staging

With the use of information from a database of pediatric patients with concomitant nuclear GFR and serum creatinine (Cr), estimated GFR equations were derived on the basis of local laboratory methods and population. These formulas then were compared with those recommended by the National Kidney Foundation for estimating GFR in children. For this, their ability to estimate accurately an individuals true GFR and chronic kidney disease stage, identify patients whose true GFR was <60 ml/min per 1.73 m(2), and to identify correctly deterioration in an individuals GFR over time was compared. Next, two methods to estimate GFR in children without the use of height or weight were developed. The first was a height- and weight-independent formula; the second was a novel approach using the Schwartz formula and calculating a Cr cutoff based on age-based estimates of height and GFR level of interest, i.e., <60 ml/min per 1.73 m(2). Our results suggest that if local laboratory constants are derived and a height is known, then the Schwartz formula offers the most accuracy with least mathematical complexity to perform in the clinical setting. If height is not available but the local laboratory constants have been derived, then the British Columbias Childrens Hospital 2 formula is of value; however, in the setting of estimating pediatric renal function in the outpatient laboratory, where neither of these factors is commonly known, an approach whereby a Cr cutoff for a GFR of interest is developed is suggested. Provided are Cr levels that are based on a reference method of Cr measurement to facilitate this approach for the clinician.

An evaluation of the decision-making process regarding amniocentesis following a screen-positive maternal serum screen result.

To identify the decision‐making factors and personal characteristics of women who opt for and against amniocentesis following a screen‐positive maternal serum screen (MSS) result.

Practice patterns of mitochondrial disease physicians in North America. Part 1: diagnostic and clinical challenges.

Mitochondrial medicine is a young subspecialty. Clinicians have a limited evidence base on which to formulate clinical decisions regarding diagnosis, treatment and patient management. Mitochondrial medicine specialists have cobbled together an informal set of rules and paradigms for preventive care and management based in part on anecdotal experience. The Mitochondrial Medicine Society (MMS) assessed the current state of clinical practice from diagnosis, to preventive care and treatment, as provided by various mitochondrial disease specialists in North America. We hope that by obtaining this information we can begin moving towards formulating a set of consensus criteria and establishing standards of care.

Eye movement and diffusion tensor imaging analysis of treatment effects in a Niemann-Pick Type C patient

New treatment options for Niemann-Pick Type C (NPC) have recently become available. To assess the efficiency and efficacy of these new treatment markers for disease status and progression are needed. Both the diagnosis and the monitoring of disease progression are challenging and mostly rely on clinical impression and functional testing of horizontal eye movements. Diffusion tensor imaging (DTI) provides information about the microintegrity especially of white matter. We show here in a case report how DTI and measures derived from this imaging method can serve as adjunct quantitative markers for disease management in Niemann-Pick Type C. Two approaches are taken--first, we compare the fractional anisotropy (FA) in the white matter globally between a 29-year-old NPC patient and 18 healthy age-matched controls and show the remarkable difference in FA relatively early in the course of the disease. Second, a voxelwise comparison of FA values reveals where white matter integrity is compromised locally and demonstrate an individualized analysis of FA changes before and after 1year of treatment with Miglustat. This method might be useful in future treatment trials for NPC to assess treatment effects.

Practice patterns of mitochondrial disease physicians in North America. Part 2: treatment, care and management.

Mitochondrial medicine is a young subspecialty. Clinicians have limited evidence-based guidelines on which to formulate clinical decisions regarding diagnosis, treatment and management for patients with mitochondrial disorders. Mitochondrial medicine specialists have cobbled together an informal set of rules and paradigms for preventive care and management based in part on anecdotal experience. The Mitochondrial Medicine Society (MMS) assessed the current state of clinical practice including diagnosis, preventive care and treatment, as provided by various mitochondrial disease providers in North America. In this second of two reports, we present data related to clinical practice that highlight the challenges clinicians face in the routine care of patients with established mitochondrial disease. Concerning variability in treatment and preventative care approaches were noted. We hope that sharing this information will be a first step toward formulating a set of consensus criteria and establishing standards of care.

Cross-Sectional Associations of Serum Perfluoroalkyl Acids and Thyroid Hormones in U.S. Adults: Variation According to TPOAb and Iodine Status (NHANES 2007–2008)

Background: Perfluoroalkyl acids (PFASs) are suspected thyroid toxicants, but results from epidemiological studies are inconsistent. Objectives: We examined associations between serum PFASs and thyroid hormones (THs) in a representative, cross-sectional sample of U.S. adults. We hypothesized that people with high thyroid peroxidase antibodies and low iodine would be more susceptible to PFAS-induced thyroid disruption. Methods: Our sample included 1,525 adults (≥ 18 years) from the 2007–2008 NHANES study with available serum PFASs and THs. We examined associations between four serum PFASs [perfluorohexane sulfonate (PFHxS), perfluorononanoate (PFNA), perfluorooctanoate (PFOA), and perfluorooctane sulfonate (PFOS)], and serum THs [free triiodothyronine (fT3), free thyroxine (fT4), fT3/fT4, thyroid-stimulating hormone (TSH), total T3 (TT3), and total T4 (TT4)] using multivariable linear regression. We stratified subjects into four groups by two indicators of thyroid “stress”: thyroid peroxidase antibody (TPOAb ≥ 9 IU/mL) and iodine status (< 100 μg/L urine). Results: Of 1,525 participants, 400 (26%) had low iodine only (T0I1), 87 (6%) had high TPOAb only (T1I0), and 26 (2%) had both high TPOAb and low iodine (T1I1). In general, associations were similar among participants in the groups with neither (T0I0) or only one thyroid stressor (T0I1 or T1I0), suggesting that PFAS–TH associations were not modified by high TPOAb or low iodine alone. However, PFHxS and PFOS were negatively associated (p < 0.05) with fT4, and all four PFASs were positively associated (p < 0.05) with fT3, fT3/fT4, TSH, and TT3 in the group with joint exposure to high TPOAb and low iodine (T1I1). Conclusions: We found evidence of PFAS-associated thyroid disruption in a subset of U.S. adults with high TPOAb (a marker of autoimmune hypothyroidism) and low iodine status, who may represent a vulnerable subgroup. However, the small sample size, cross-sectional design, and possibility of reverse causation are limitations of this work. Citation: Webster GM, Rauch SA, Ste Marie N, Mattman A, Lanphear BP, Venners SA. 2016. Cross-sectional associations of serum perfluoroalkyl acids and thyroid hormones in U.S. adults: variation according to TPOAb and iodine status (NHANES 2007–2008). Environ Health Perspect 124:935–942; http://dx.doi.org/10.1289/ehp.1409589

Antiglycine receptor antibody and encephalomyelitis with rigidity and myoclonus (PERM) related to small cell lung cancer.

A 39-year-old man (a lifetime non-smoker) presented with a locked left jaw and leg myoclonus. Clinical and electromyographic findings were in keeping with progressive encephalomyelitis with rigidity and myoclonus (PERM) syndrome. A thoracic CT scan demonstrated a 19 mm right hilar nodule, which was proven to be small cell lung cancer on bronchoscopic biopsy. Serological evaluation of the patients plasma revealed antibodies against glycine receptors (serology negative for anti-GAD, anti-Yo, anti-Hu, anti-Ri, antiamphiphysin, anti-Ma2/Ta, anti-CRMP5 and anti-NMDA receptor). After his cancer was treated with chemotherapy and intravenous immunoglobulins (IVIg), neurological symptoms resolved but returned several months later without any evidence of cancer recurrence. Symptoms were refractory to corticosteroids and IVIg therapy. Rituximab was then initiated, which led to a dramatic and sustained resolution of symptoms. To our knowledge, this is the first case of PERM related to antiglycine receptor antibodies from paraneoplastic syndrome, which resolved with rituximab.

Emphysema in an adult with galactosialidosis linked to a defect in primary elastic fiber assembly.

Galactosialidosis is a lysosomal storage disorder caused by loss of function of protective protein cathepsin A, which leads to secondary deficiencies of β-galactosidase and neuraminidase-1. Emphysema has not been previously reported as a possible complication of this disorder, but we now describe this condition in a 41-year-old, non-smoking male. Our patient did not display deficiency in α-1-antitrypsin, the most common cause of emphysema in non-smokers, which brings about disseminated elastolysis. We therefore hypothesized that loss of cathepsin A activity was responsible because of previously published evidence showing it is prerequisite for normal elastogenesis. We now present experimental evidence to support this theory by demonstrating impaired primary elastogenesis in cultures of dermal fibroblasts from our patient. The obtained data further endorse our previous finding that functional integrity of the cell surface-targeted molecular complex of cathepsin A, neuraminidase-1 and the elastin-binding protein (spliced variant of β-galactosidase) is prerequisite for the normal assembly of elastic fibers. Importantly, we also found that elastic fiber production was increased after exposure either to losartan, spironolactone, or dexamethasone. Of immediate clinical relevance, our data suggest that surviving patients with galactosialidosis should have periodic assessment of their pulmonary function. We also encourage further experimental exploration of therapeutic potential of the afore-mentioned elastogenesis-stimulating drugs for the alleviation of pathological processes in galactosialidosis that could be mechanistically linked to impaired deposition of elastic fibers.

Monitoring Renal Function in Hypertensive Pregnancy

Objective. In hypertensive pregnancy, to compare 24hr creatinine clearance (CrCl) with formulae-derived renal function (Cockcroft-Gault (CG) or Modified Diet in Renal Disease (MDRD)). Study design. Retrospective review (198 women, 63% preeclampsia) using paired t-test (significant p < 0.008) and intraclass correlation coefficients (acceptable >0.70) to compare 24hr and CG CrCl. The 24hr CrCl was compared with each of the CG and MDRD formulae by Bland-Altman plots. Results. For 24hr CrCl, uncorrected values were similar to corrected using pre-pregnancy weight (p = 0.04); other weights gave consistently different CrCl (p < 0.0001). Limits of agreement were wide when CG and MDRD formulae were compared with 24hr CrCl. Compared with 24hr CrCl, MDRD estimates were consistently lower, and CG CrCl higher (current weight) or lower (pre-pregnancy or lean weight). Conclusion. MDRD and CG formulae should not be used in hypertensive pregnancy. Use of serum creatinine is advocated. If 24hr CrCl is performed, any correction should utilize pre-pregnancy weight. Neither the Cockcroft-Gault nor Modified Diet in Renal Disease formulae for glomerular filtration rate estimation are alternatives to 24hr creatinine clearance in hypertensive pregnancy.