Andre Mattman

Current evidence suggests that iron deficiency (ID) plays a key role in the pathogenesis of conditions presenting with restlessness such as attention deficit hyperactivity disorder (ADHD) and restless legs syndrome (RLS). In clinical practice, ID and iron supplementation are not routinely considered in the diagnostic work-up and/or as a treatment option in such conditions. Therefore, we conducted a scoping literature review of ID guidelines. Of the 58 guidelines included, only 9 included RLS, and 3 included ADHD. Ferritin was the most frequently cited biomarker, though cutoff values varied between guidelines and depending on additional factors such as age, sex, and comorbidities. Recommendations surrounding measurable iron biomarkers and cutoff values varied between guidelines; moreover, despite capturing the role of inflammation as a concept, most guidelines often did not include recommendations for how to assess this. This lack of harmonization on the interpretation of iron and inflammation biomarkers raises questions about the applicability of current guidelines in clinical practice. Further, the majority of ID guidelines in this review did not include the ID-associated disorders, ADHD and RLS. As ID can be associated with altered movement patterns, a novel consensus is needed for investigating and interpreting iron status in the context of different clinical phenotypes.

Objective: Adult‐onset Still's disease (AOSD) and secondary hemophagocytic lymphohistiocytosis (sHLH) are both hyperferritinemic cytokine storm syndromes that can be difficult to distinguish from each other in hospitalized patients. The objective of this study was to compare the inflammatory markers ferritin, D‐dimer, C‐reactive protein (CRP), and soluble CD25 (sCD25) in patients with AOSD and sHLH. These four markers were chosen as they are widely available and represent different aspects of inflammatory diseases: macrophage activation (ferritin); endothelialopathy (D‐dimer); interleukin‐1/interleukin‐6/tumour necrosis factor elevation (CRP) and T cell activation (sCD25).Methods: This was a single‐center retrospective study. Patients diagnosed by the Hematology service at Vancouver General Hospital for AOSD or sHLH from 2009 to 2023 were included.Results: There were 16 AOSD and 44 sHLH patients identified. Ferritin was lower in AOSD than HLH (median 11 360 μg/L vs. 29 020 μg/L, p = .01) while D‐dimer was not significantly different (median 5310 mg/L FEU vs. 7000 mg/L FEU, p = .3). CRP was higher (median 168 mg/L vs. 71 mg/L, p <.01) and sCD25 was lower (median 2220 vs. 7280 U/mL, p = .004) in AOSD compared to HLH. The combined ROC curve using CRP >130 mg/L and sCD25< 3900 U/mL to distinguish AOSD from HLH had an area under the curve (AUC) of 0.94 (95% confidence interval 0.93–0.97) with sensitivity 91% and specificity 93%.Conclusions: These findings suggest that simple, widely available laboratory tests such as CRP and sCD25 can help clinicians distinguish AOSD from HLH in acutely ill adults with extreme hyperferritinemia. Larger studies examining a wider range of clinically available inflammatory biomarkers in a more diverse set of cytokine storm syndromes are warranted.

A 46-year-old man was admitted to intensive care with sepsis from acute cholangitis associated with cholelithiasis. He was stabilized with antibiotics and endoscopic retrograde cholangiopancreatography with stenting. During his admission, he was found to have diffuse weakness and pain more over his proximal muscles and over his hips bilaterally. He had no skin rash, extra-myopathic clinical features, or signs of a viral prodrome. His creatine kinase (CK) was >25 000 U/L. His atorvastatin was then stopped. His rheumatoid, lupus, antineutrophilic cytoplasmic antibody (ANCA), and infectious serology were normal as were thyroid-stimulating hormone (TSH) and malignancy screening. His thigh magnetic resonance imaging revealed bilateral symmetric edema suggestive of myositis. His electromyography showed severe sensory motor polyneuropathy along with proximal myopathy with inflammatory features involving both the upper and lower extremities. Necrotizing myopathy with an inflammatory component was identified in his muscle biopsy. His myositis panel was negative for anti-3-hydroxy-3-methylglutaryl coenzyme A reductase (anti-HMGCR) and anti-signal recognition particle (anti-SRP). He was diagnosed with seronegative immune-mediated necrotizing myositis. He was treated with steroids, intravenous immunoglobulin, and azathioprine. His CK recovered ( Fig. 1), along with an improvement in symptoms.

Background and Aim: Patients suspected of Alpha 1-Antitrypsin (A1AT) ab-normality based on low serum concentration are routinely confirmed through polymerase chain reaction (PCR) testing of peripheral blood. Genotyping for-malin-fixed paraffin-embedded (FFPE) tissue is a novel approach that could aid in detecting variant A1AT. We performed qPCR on FFPE liver explants with Periodic Acid Schiff after Diastase (PASD)- and A1AT-positive globules to confirm and estimate the frequency of A1AT deficiency in transplant cases. Materials and Methods: Eighteen (12.68%) of 142 patients with end-stage liver disease showed PASD/A1AT positive globules. FFPE of the explants was tested through qPCR to detect S and Z alleles. A second age- and sex-matched control group consisting of five liver transplant patients with neg-ative globules was included in the study. Results: qPCR assay was successful with all the samples meeting QC pa-rameters. All patients included in the study elucidated Z allele variants; 2 homozygous (11.1%) and 16 heterozygous (88.9%). The control group demonstrated normal wild-type MM allele. Conclusion: Screening for A1AT deficiency using serum levels is not suffi-ciently sensitive to detect deficiency, especially in carriers. If A1AT testing was not performed preoperatively and the risk is high based on the PASD/A1AT-positive globules in the explants, then molecular testing of FFPE tis-sue can be a viable method for confirming the diagnosis.

Large single mitochondrial DNA (mtDNA) deletion syndrome is a rare inborn error of metabolism with variable heteroplasmy levels and clinical phenotype among affected individuals. Chronic progressive external ophthalmoplegia (CPEO) is the most common phenotype in adults with this form of mitochondrial disease [J Intern Med. 2020;287(6):592–608 and Biomed Rep. 2016;4(3):259–62]. The common CPEO clinical manifestations are ptosis and ophthalmoplegia. More variable phenotypic manifestations of CPEO (CPEO plus) include involvement of the peripheral nervous system and myopathy. Here, we describe a 62-year-old female with CPEO and the major mtDNA deletion present at 40% heteroplasmy, who had a coexistent previously undescribed CPEO phenotypic feature of persistent unexplained macrocytosis without anemia. Building on this case, we reviewed other major mtDNA deletion cases seen in our Adult Metabolic Diseases Clinic (AMDC) at the University of British Columbia, Vancouver, Canada, from 2016 to 2022. The major mtDNA deletion cases (n = 26) were compared with mtDNA missense variants identified in the clinic over the same period who acted as the comparison group (n = 16). Of these, the most frequent diagnosis was maternally inherited diabetes and deafness and mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes. Ten out of 26 (38%) of mtDNA deletion patients had macrocytosis with elevated mean corpuscular volume (MCV), median (interquartile range) of 108 fL (102–114 fL). Seven of the patients with macrocytosis had no pertinent etiology. None of the comparison group had macrocytosis. There was a significant difference (p = 0.000) between the MCV and MCH in the mtDNA deletion group compared to the comparison group. This communication sheds light on the association of macrocytosis with the mtDNA deletion syndrome. It would be of great interest to determine if the association is found in other mitochondrial disease clinic populations.

Nesidioblastosis is a rare pancreatic disorder involving enlarged beta cells throughout the pancreas, causing elevated insulin production. We present the case of a 53-year-old woman with the initial symptom of fasting hypoglycemia. No pancreatic lesions were indicated on computed tomography and magnetic resonance imaging scans, and an octreotide scan was negative for insulinoma. Selective arterial calcium stimulation (SACST) showed increased insulin production from the stimulation of 3 out of 5 arteries. The SACST results suggested a diagnosis of nesidioblastosis, which was confirmed by histopathology after a subtotal distal pancreatectomy. The patient has normal glucose tolerance after surgery with no further problems of hypoglycemia, indicating that this is a rare case of nesidioblastosis extending only partially through the pancreas.

Serum IgG subclasses (IgGSC) are measured for a number of indications, but the most common are the identification of selective immunodeficiency disease and the diagnosis of IgG4-related disease (IgG4RD). Traditional nephelometric (IN) assays can suffer from two issues impacting the accuracy of the results: (1) hook effect and (2) antibody cross-reactivity between the subclasses. Liquid chromatography–tandem mass spectrometry (LC–MS/MS) is not vulnerable to these modes of interference and therefore serves as an excellent and relatively inexpensive means of diagnosing and/or monitoring the relevant clinical conditions. We describe a semiautomated and simple method for the accurate and precise measurement of IgGSC from 20 μL of serum using a liquid chromatography and tandem mass spectrometry (LC–MS/MS) method following digestion of serum proteins in 96-well plate format. Due to the high abundance of the target proteins, no specialized sample preparation (such as solid phase extraction) is required. Twenty microliters are injected to the LC–MS/MS system. Quantitation is performed against a five-point duplicate linear calibration curve prepared in blank matrix. The assay calibration range is 0.38–7.74 g/L for IgG1, 0.24–4.46 g/L for IgG2, 0.038–0.752 g/L for IgG3, 0.025–0.435 g/L for IgG4, and 0.62–15.5 g/L for total IgG. Total IgG is used as an internal quality control marker and is compared to the sum of the four subclass results. Total imprecision in clinical production has been observed to be 5.1–10.6% for in-house prepared control materials having IgGSC mean values in the range of 0.38–8.43 g/L for IgG1, 0.22–3.76 g/L for IgG2, 0.0387–0.721 g/L for Ig3, and 0.0279–1.46 g/L for IgG4. Limit of quantitation (LoQ) was determined to be 0.29 g/L for IgG1, 0.22 g/L for IgG2, 0.019 g/L for IgG3, and 0.0067 g/L for IgG4. Key words Immunoglobulin G IgG subclasses Mass spectrometry IgG4RD

To the editor, We read with interest the manuscript by Parker et al. ( 1) describing the impact of glucose meter vendor selection on the detection of neonatal hypoglycemia. In British Columbia (BC), we recently switched from one major vendor (Roche Accu-Chek Inform II™) to another (Nova StatStrip™). As part of the implementation, a formal comparison of the Nova meter to a reference method (The reference method is based on the Glucose Committee of the American Association for Clinical Chemistry and the Centers for Disease Control and Prevention) also identified 0.3 mmol/L (same magnitude as noted by Parker et al. ( 1)), as a suitable bias correction factor for Nova glucose results based on strip lots currently in use in BC. This correction factor (+0.3 mmol/L) was selected to optimize the hypoglycemic range (<4.0 mmol/L) but applied uniformly to all glucose results via the glucose meter middleware....